Tachykinin receptor antagonists

ABSTRACT

The present invention relates to selective NK-1 receptor antagonists of Formula (I); or a pharmaceutically acceptable salt thereof, for the treatment of disorders associated with an excess of tachykinins

This application is a 371 of PCT/US03/10682 filed Apr. 22, 2003, whichclaims benefit of U.S. Provisional Application 60/376,121 filed Apr. 26,2002 and claims benefit of U.S. Provisional Application 60/440,865,filed Jan. 16, 2003.

The present invention provides compounds of Formula (I), compositionsthereof, and a method of antagonizing the NK-1 subtype of tachykininreceptor that comprises administering to a patient in need thereof aneffective amount of a compound of Formula (I). In addition, the presentinvention relates to processes for preparing the compounds of Formula Iand intermediates thereof.

BACKGROUND OF THE INVENTION

Tachykinins are a family of peptides that are widely distributed in boththe central and peripheral nervous systems. These peptides exert anumber of biological effects through actions at tachykinin receptors. Todate, three such receptors have been characterized, including the NK-1,NK-2, and NK-3 subtypes of tachykinin receptor.

The role of the NK-1 receptor subtype in numerous disorders of thecentral nervous system and the periphery has been thoroughlydemonstrated in the art. For instance, NK-1 receptors are believed toplay a role in depression, anxiety, and central regulation of variousautonomic, as well as cardiovascular and respiratory functions. NK-1receptors in the spinal cord are believed to play a role in paintransmission, especially the pain associated with migraine andarthritis. In the periphery, NK-1 receptor activation has beenimplicated in numerous disorders, including various inflammatorydisorders, asthma, and disorders of the gastrointestinal andgenitourinary tract.

There is an increasingly wide recognition that selective NK-1 receptorantagonists would prove useful in the treatment of many diseases of thecentral nervous system and the periphery. While many of these disordersare being treated by new medicines, there are still many shortcomingsassociated with existing treatments. For example, the newest class ofanti-depressants, selective serotonin reuptake inhibitors (SSRIs), areincreasingly prescribed for the treatment of depression; however, SSRIshave numerous side effects, including nausea, insomnia, anxiety, andsexual dysfunction. This could significantly affect patient compliancerate. As another example, current treatments for chemotherapy-inducednausea and emesis, such as the 5-HT₃ receptor antagonists, areineffective in managing delayed emesis. The development of NK-1 receptorantagonists will therefore greatly enhance the ability to treat suchdisorders more effectively. Thus, the present invention provides a classof potent, non-peptide NK-1 receptor antagonists, compositionscomprising these compounds, and methods of using the compounds.

BRIEF SUMMARY OF THE INVENTION

The invention provides compounds of Formula (I):

wherein:

-   D¹ is a C₁–C₃ alkane-diyl;-   D² is CH or nitrogen;-   D⁴ is oxygen or sulfur;-   R¹ is phenyl,    -   which is optionally substituted with one to three substitutents        independently selected from the group consisting of halo, C₁–C₄        alkyl, C₁–C₄ alkoxy, cyano, difluoromethyl, trifluoromethyl, and        trifluoromethoxy;-   R⁴ is a radical selected from the group consisting of:

wherein

-   A¹, A², A³, and A⁴, together with the atoms to which they are    attached, form an unsaturated heterocyclic ring in which each of A¹,    A², and A³ is independently CR⁷, nitrogen, which nitrogen is    optionally substituted with R⁸, oxygen, or sulfur, and A⁴ is carbon    or nitrogen, wherein only one of A¹, A², and A³ can be oxygen or    sulfur;-   A⁵, A⁶, A⁷, and A⁸, together with the atoms to which they are    attached, form an unsaturated carbocyclic or heterocyclic ring in    which each of A⁵, A⁶, A⁷, and A⁸ is independently CR⁷ or nitrogen,    wherein at least one of A⁵, A⁶, A⁷, and A⁸ must be CR⁷;    -   each R⁷ is independently selected from the group consisting of        hydrogen, halo, C₁–C₄ alkyl, substituted C₁–C₄ alkyl, C₃–C₆        cycloalkyl, C₁–C₄ alkoxycarbonyl, trifluoromethyl,        trifluoromethoxy, and —NR⁹R¹⁰;        -   R⁹ and R¹⁰ are each independently hydrogen, C₁–C₄ alkyl, or            —C(O)—CH₃, or R⁹ and R¹⁰, together with the nitrogen to            which they are attached, form a 4–7 membered saturated            heterocyclic ring;    -   each R⁸ is independently selected from the group consisting of        hydrogen, C₁–C₄ alkyl, substituted C₁–C₄ alkyl, and C₁–C₃        cycloalkyl;-   R⁶ is C₁–C₄ alkyl, C₃–C₆ cycloalkyl, phenyl, or pyridyl,    -   which phenyl or pyridyl is optionally substituted with one to        three substituents independently selected from the group        consisting of halo, cyano, C₁–C₄ alkyl, C₁–C₄ alkoxy,        trifluoromethyl, trifluoromethoxy, and —NR¹¹R¹²;    -   R¹¹ and R¹² are each independently hydrogen or C₁–C₄ alkyl, or        R¹¹ and R¹², together with the nitrogen to which they are        attached, form a 4–7 membered saturated heterocyclic ring;-   R⁵ is hydrogen, halo, trifluoromethyl, C₁–C₄ alkyl, C₃–C₆    cycloalkyl, furyl, thienyl, pyrrolyl, imidazolyl, —NR¹³R¹⁴,    pyridyloxy, phenyl, phenoxy, phenylthio, anilino,    -   which phenyl, phenoxy, phenylthio, or anilino group may be        optionally substituted on the phenyl ring with one or two        substituents independently selected from the group consisting of        halo, C₁–C₄ alkyl, C₁–C₄ alkoxy, and —S(O)_(q)(C₁–C₄ alkyl),        or a radical selected from the group consisting of:

wherein

-   W is a bond, CHR¹⁵, O, NR¹⁵, or S(O)_(q);    -   q is 0, 1, or 2;    -   R¹⁵ is selected from the group consisting of hydrogen, C₁–C₄        alkyl, acetyl, carbamoyl, phenyl, benzyl, and —S(O)₂CH₃;-   Z¹, Z², and Z³ are each independently CH or nitrogen;-   R¹³ and R¹⁴ are each independently hydrogen or C₁–C₄ alkyl;    or a pharmaceutically acceptable salt thereof.

The compounds of Formula I are antagonists of tachykinin receptors.Specifically, the compounds of Formula I are antagonists of the NK-1subtype of tachykinin receptor. Because these compounds inhibit thephysiological effects associated with an excess of tachykinins, thecompounds are useful in the treatment of numerous disorders related totachykinin receptor activation. These disorders include: anxiety,depression, psychosis, and schizophrenia and other psychotic disorders;neurodegenerative disorders such as dementia, including senile dementiaof the Alzheimer's type, Alzheimer's disease, AIDS-associated dementia,and Down's syndrome; seizure disorders, such as epilepsy; demyelinatingdiseases such as multiple sclerosis and amyotrophic lateral sclerosisand other neuropathological disorders, such as peripheral neuropathy,diabetic and chemotherapy-induced neuropathy, and post-herpetic andother neuralgias; acute and chronic obstructive airway diseases such asadult respiratory distress syndrome, bronchopneumonia, bronchospasm,chronic bronchitis, drivercough, and asthma; inflammatory diseases suchas inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis,and rheumatoid arthritis; disorders of the musculo-skeletal system, suchas osteoporosis; allergies such as eczema and rhinitis; hypersensitivitydisorders such as poison ivy; ophthalmic diseases such asconjunctivitis, vernal conjunctivitis, and the like; cutaneous diseasessuch as contact dermatitis, atopic dermatitis, urticaria, and othereczematoid dermatites; addiction disorders such as alcoholism;stress-related somatic disorders; reflex sympathetic dystrophy such asshoulder/hand syndrome; dysthymic disorders; adverse immunologicalreactions such as rejection of transplanted tissues and disordersrelated to immune enhancement or suppression such as systemic lupuserythematosis; gastrointestinal disorders or diseases associated withthe neuronal control of viscera such as ulcerative colitis, Crohn'sdisease and irritable bowel syndrome; disorders of bladder function suchas bladder detrusor hyper-reflexia and incontinence; atherosclerosis;fibrosin and collagen diseases such as scleroderma and eosinophilicfascioliasis; irritative symptoms of benign prostatic hypertrophy;disorders associated with blood pressure, such as hypertension; ordisorders of blood flow caused by vasodilation and vasospastic diseases,such as angina, migraine, and Reynaud's disease; emesis, includingchemotherapy-induced nausea and emesis; and pain or nociception, forexample, that attributable to or associated with any of the foregoingconditions.

In one embodiment, this invention provides a pharmaceutical compositioncomprising, as an active ingredient, a compound of Formula I, or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers, diluents, or excipients.

In a further embodiment, the present invention relates to a method ofmaking a compound represented by Formula I, and intermediates thereof.

In another embodiment, the present invention provides a method ofselectively antagonizing an NK-1 receptor by contacting the receptorwith a compound of Formula I, or a pharmaceutically acceptable saltthereof.

In another embodiment, this invention provides methods of treating acondition associated with an excess of tachykinins, comprising:administering to a patient in need thereof an effective amount of acompound of Formula I, or a pharmaceutically acceptable salt thereof.That is, the present invention provides for the use of a compound ofFormula I, or a pharmaceutical composition thereof, for the treatment ofa disorder associated with an excess of tachykinins.

In another aspect, the present invention provides for the use of acompound of Formula I, or a pharmaceutically acceptable salt thereof, inthe manufacture of a medicament for antagonizing the NK-1 receptor.Thus, the present invention provides for the use of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment of a disorder associatedwith an excess of tachykinins by means of the method described above.

Of the disorders listed above, depression, anxiety, schizophrenia andother psychotic disorders, emesis, pain, asthma, inflammatory boweldisease, irritable bowel syndrome, and dermatitis are of importance. Ofthese disorders, depression and anxiety are of particular importance.

Thus, in a preferred embodiment, the present invention provides a methodfor treating major depressive disorder, comprising: administering to apatient in need thereof an effective amount of a compound of Formula I,or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, the present invention provides a methodfor treating generalized anxiety disorder, comprising: administering toa patient in need thereof an effective amount of a compound of FormulaI, or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, the present invention provides a methodfor treating panic disorder, comprising: administering to a patient inneed thereof an effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.

In another preferred embodiment, the present invention provides a methodfor treating obsessive compulsive disorder, comprising: administering toa patient in need thereof an effective amount of a compound of FormulaI, or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, the present invention provides a methodfor treating social phobia, comprising: administering to a patient inneed thereof an effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.

In another preferred embodiment, the present invention provides a methodfor treating irritable bowel syndrome, comprising: administering to apatient in need thereof an effective amount of a compound of Formula I,or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, the present invention provides a methodfor treating inflammatory bowel disease, comprising: administering to apatient in need thereof an effective amount of a compound of Formula I,or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, the present invention provides a methodfor treating emesis (chemotherapy-induced nausea and acute or delayedemesis), comprising: administering to a patient in need thereof aneffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The terms and abbreviations used in the preparations and examples havetheir normal meanings unless otherwise designated. For example “° C.”refers to degrees Celsius; “N” refers to normal or normality; “mol”refers to mole or moles; “h” refers to hour(s); “eq” refers toequivalent; “g” refers to gram or grams; “L” refers to liter or liters;“M” refers to molar or molarity; “brine” refers to a saturated aqueoussodium chloride solution; “J” refers to hertz; “ES” refers toelectrospray; “MS” refers to mass spectrometry; “NMR” refers to nuclearmagnetic resonance spectroscopy; “TLC” refers to thin layerchromatography; “ACN” refers to acetonitrile; “DMF” refers toN,N-dimethylformamide; “DMSO” refers to dimethylsulfoxide; “Et₂O” refersto diethyl ether; “EtOAc” refers to ethyl acetate; “MeOH” refers tomethanol; “EtOH” refers to ethanol; “iPrOH” refers to isopropanol; “TEA”refers to triethylamine; “TFA” refers to trifluoroacetic acid; “THF”refers to tetrahydrofuran.

As used herein, the term “C₁–C₄ alkyl” refers to straight or branched,monovalent, saturated aliphatic chains of 1 to 4 carbon atoms andincludes, but is not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, and tert-butyl. The terms “C₁–C₃ alkyl” and“C₁–C₂ alkyl” are encompassed within the definition of “C₁–C₄ alkyl.”

The term “substituted C₁–C₄ alkyl” refers to a straight or branched,monovalent, saturated aliphatic chain of 1 to 4 carbon atoms, asencompassed in the definition of C₁–C₄ alkyl above, that is furthersubstituted on any of the carbon atoms with one to three substituentsindependently selected from the group consisting of hydroxy, oxo, halo,C₁–C₄ alkoxy, ═N(OH), and —NR^(a)R^(b), wherein R^(a) is H or C₁–C₄alkyl, R^(b) is H, C₁–C₄ alkyl, or —C(O)—CH₃, or R^(a) and R^(b),together with the N to which they are attached, form a 4–7 memberedsaturated heterocyclic ring. Examples of such 4–7 membered saturatedheterocyclic rings include, but are not limited to, pyrrolidinyl,piperidino, and morpholino.

“C₁–C₄ alkane-diyl” refers to a straight or branched, divalent,saturated aliphatic chain of 1 to 4 carbon atoms and includes, but isnot limited to, methylene, ethylene, ethane-1,1-diyl, propane-1,1-diyl,propane-1,2-diyl, propane-1,3-diyl, propane-2,2-diyl, andbutane-1,4-diyl. The terms “C₁–C₂ alkane-diyl” and “C₁–C₃ alkane-diyl”are encompassed within the definition of “C₁–C₄ alkane-diyl.”

“C₁–C₄ alkoxy” represents a C₁–C₄ alkyl group, as defined above, linkedto the parent molecule through an oxygen atom. Typical C₁–C₄ alkoxygroups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy,tert-butoxy, and the like. The term “C₁–C₄ alkoxy” includes within itsdefinition the term “C₁–C₃ alkoxy” and “C₁–C₂ alkoxy.”

“C₃–C₆ cycloalkyl” represents a saturated hydrocarbon ring structurecontaining from three to six carbon atoms. Typical C₃–C₆ cycloalkylgroups include cyclopropyl, cyclopentyl, cyclohexyl, and the like.

“Halo,” “halogen,” and “halide” represent a chloro, fluoro, bromo oriodo atom. Preferred halogens include chloro and fluoro.

“C₁–C₄ alkoxycarbonyl” represents a straight or branched C₁–C₄ alkoxychain, as defined above, that is attached via the oxygen atom of thealkoxy to a carbonyl moiety. Typical C₁–C₄ alkoxycarbonyl groups includemethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, t-butoxycarbonyl and the like.

The term “Pg” refers to an alcohol, carboxyl, or amino protecting group.Typical protecting groups include tetrahydropyranyl (THP), silanes suchas trimethylsilane (TMS), tert-butyldimethylsilane (TBDMS), andtert-butyldiphenylsilane (TBDPS), methoxymethyl (MOM), benzyl (Bn),p-methoxybenzyl, formyl, acetyl (Ac), and tert-butoxycarbonyl (t-BOC).Typical carboxyl protecting groups may include methyl, ethyl, andtert-butyl. The selection and use of protecting groups is well known andappreciated in the art. See for example, Protecting Groups in OrganicSynthesis, Theodora Greene (Wiley-Interscience); Protecting Groups,Philip J. Kocienski, Thieme Medical Publishers, inc: New York 1994,chapters 2, 4, 6.

It is understood that when R⁵ or R⁶ is pyridyl, the radical may be apyridin-2-yl, pyridin-3-yl, or pyridin-4-yl. When R⁵ is furyl orthienyl, the radical may be attached at the 2-, or 3-position of theradical. When R⁵ is pyrrolyl or imidazolyl, the radical may be attachedat the 1-, 2-, or 3 position of the pyrrolyl, or the 1, 2, or 4 positionof the imidazolyl.

The skilled artisan will recognize that when R⁴ is a radical of Formula(IA), and A¹, A², or A³ is nitrogen, the nitrogen may only be optionallysubstituted with R⁸ when such substitution creates an unchargedheterocyclic ring.

The compounds of the present invention may exist as stereoisomers. TheCahn-Prelog-Ingold designations of (R)- and (S)- and the designations ofL- and D- for stereochemistry relative to the isomers of glyceraldehydeare used herein to refer to specific isomers. The specific stereoisomerscan be prepared by stereospecific synthesis or can be resolved andrecovered by techniques known in the art, such as chromatography onchiral stationary phases, and fractional recrystallization of additionsalts formed by reagents used for that purpose. Useful methods ofresolving and recovering specific stereoisomers are known in the art anddescribed in E. L. Eliel and S. H. Wilen, Stereochemistry of OrganicCompounds, (Wiley-Interscience 1994), and J. Jacques, A. Collet, and S.H. Wilen, Enantiomers, Racemates, and Resolutions, Wiley-Interscience1981). It is understood that the present invention contemplates allenantiomers and mixtures of enantiomers, including racemates.

The skilled artisan will recognize that compounds of the presentinvention may exist as tautomers. It is understood that tautomeric formsof the compounds of Formula (I) are also encompassed in the presentinvention.

This invention includes the pharmaceutically acceptable salts of thecompounds of Formula I. A compound of this invention can possess asufficiently basic functional group, which can react with any of anumber of inorganic and organic acids, to form a pharmaceuticallyacceptable salt.

The term “pharmaceutically-acceptable salt” as used herein, refers to asalt of a compound of the above Formula I. It should be recognized thatthe particular counterion forming a part of any salt of this inventionis usually not of a critical nature, so long as the salt as a whole ispharmacologically acceptable and as long as the counterion does notcontribute undesired qualities to the salt as a whole.

The compounds of Formula I and the intermediates described herein formpharmaceutically-acceptable acid addition salts with a wide variety oforganic and inorganic acids and include the physiologically-acceptablesalts which are often used in pharmaceutical chemistry. Such salts arealso part of this invention. A pharmaceutically-acceptable acid additionsalt is formed from a pharmaceutically-acceptable acid, as is well knownin the art. Such salts include the pharmaceutically acceptable saltslisted in Journal of Pharmaceutical Science, 66, 2–19 (1977), which areknown to the skilled artisan. See also, The Handbook of PharmaceuticalSalts; Properties, Selection, and Use. P. H. Stahl and C. G. Wermuth(ED.s), Verlag, Zurich (Switzerland) 2002.

Typical inorganic acids used to form such salts include hydrochloric,hydrobromic, hydriodic, nitric, sulfuric, phosphoric, hypophosphoric,metaphosphoric, pyrophosphoric, and the like. Salts derived from organicacids, such as aliphatic mono and dicarboxylic acids, phenyl substitutedalkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromaticacids, aliphatic and aromatic sulfonic acids, may also be used. Suchpharmaceutically acceptable salts thus include acetate, phenylacetate,trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate,o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate,phenylbutyrate, α-hydroxybutyrate, butyne-1,4-dicarboxylate,hexyne-1,4-dicarboxylate, caprate, caprylate, cinnamate, citrate,formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate,maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate,isonicotinate, nitrate, oxalate, phthalate, teraphthalate, propiolate,propionate, phenylpropionate, salicylate, sebacate, succinate, suberate,benzenesulfonate, p-bromobenzenesulfonate, chlorobenzenesulfonate,ethylsulfonate, 2-hydroxyethylsulfonate, methylsulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate,naphthalene-1,5-sulfonate, p-toluenesulfonate, xylenesulfonate,tartarate, and the like.

As used herein, the term “patient” refers to a mammal that is afflictedwith one or more disorders associated with excess tachykinins. Guineapigs, dogs, cats, rats, mice, horses, cattle, sheep, and humans areexamples of mammals within the scope of the meaning of the term. It willbe understood that the most preferred patient is a human. It is alsounderstood that this invention relates specifically to the inhibition ofmammalian NK-1 receptors.

It is also recognized that one skilled in the art may affect thedisorders by treating a patient presently afflicted with the disordersor by prophylactically treating a patient afflicted with the disorderswith an effective amount of the compound of Formula I. Thus, the terms“treatment” and “treating” are intended to refer to all processeswherein there may be a slowing, interrupting, arresting, controlling, orstopping of the progression of the disorders described herein, and isintended to include prophylactic treatment of such disorders, but doesnot necessarily indicate a total elimination of all disorder symptoms.

As used herein, the term “effective amount” of a compound of Formula Irefers to an amount that is effective in treating the disordersdescribed herein.

As with any group of pharmaceutically active compounds, some groups arepreferred in their end use application. Preferred embodiments of thepresent invention are discussed below.

Thus, when R⁴ is a radical of Formula (IA), preferred embodiments of theunsaturated heterocyclic rings of Formula (IA) include the following:

When R⁴ is a radical of Formula (IB), preferred embodiments of theunsaturated carbocyclic or heterocyclic rings of Formula (IB) includethe following:

Especially preferred embodiments of the compounds of Formula (I) aregiven below:

-   -   (a) D⁴ is oxygen.    -   (b) D² is nitrogen.    -   (c) D¹ is methylene.    -   (d) R¹ is phenyl, which is substituted with two substituents        selected from the group consisting of halo and trifluoromethyl.    -   (e) R¹ is 3,5-bis-trifluoromethyl-phenyl.    -   (f) R⁵ is a radical of Formula (ID).    -   (g) R⁵ is phenyl.    -   (h) R⁵ is pyridin-4-yl.    -   (i) R⁵ is pyridin-3-yl.    -   (j) R⁵ is pyrimidin-5-yl.    -   (k) R⁵ is imidazolyl.    -   (l) R⁵ is a radical of Formula (IC) in which W is O.    -   (m) R⁴ is a radical of Formula (IA).    -   (n) A¹ is CR⁷, A² is nitrogen, A³ is oxygen, and A⁴ is carbon.    -   (O) A¹ is CR⁷, A² is oxygen, A³ is nitrogen, and A⁴ is carbon.    -   (p) A¹ is oxygen, A² is CR⁷, A³ is nitrogen, and A⁴ is carbon.    -   (q) A¹ is NR⁸; A² is nitrogen, A³ is CR⁷, and A⁴ is carbon.    -   (r) R⁴ is a radical of Formula (IA-1).    -   (s) R⁴ is a radical of Formula (IA-2).    -   (t) R⁴ is a radical of Formula (IA-4).    -   (u) R⁴ is a radical of Formula (IA-9).    -   (v) R⁷ is C₁–C₄ alkyl or substituted C₁–C₄ alkyl.    -   (w) R⁷ is substituted C₁–C₄ alkyl in which the C₁–C₄ alkyl is        substituted with one hydroxy.    -   (x) R⁷ is C₃–C₆ cycloalkyl.    -   (y) R⁶ is phenyl, which is substituted with one substituent        selected from the group consisting of halo, cyano, C₁–C₄ alkyl,        C₁–C₄ alkoxy, trifluoromethyl, trifluoromethoxy, and —NR¹¹R¹².    -   (z) R⁶ is 2-chloro-phenyl.

Most preferred compounds of Formula I include:[1-(3,5-bis-trifluoromethylbenzyl)-5-imidazol-1-yl-1H-[1,2,3]triazol-4-yl]-[5-(2-chlorophenyl)-3hydroxymethyl-isoxazol-4-yl]-methanone(Example 269),[1-(3,5-bis-trifluoromethyl-benzyl)-5-imidazol-1-yl-1H-[1,2,3]triazol-4-yl]-[4-(2-chloro-phenyl)-2-cyclopropyl-oxazol-5-yl]-methanone(Example 131),[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-3-hydroxymethyl-isoxazol-4-yl]-methanone(Example 35),[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-3-hydroxymethyl-isoxazol-4-yl]-methanone(Example 39),[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-3-hydroxymethyl-isoxazol-4-yl]-methanone(Example 38),[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-3-(1-hydroxy-1-methyl-ethyl)-isoxazol-4-yl]-methanone(Example 28),[1-(3,5)-bis-trifluoromethyl-benzyl)-5-pyrimidin-5-yl-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-3-(1-hydroxy-1-methyl-ethyl)-isoxazol-4-yl]-methanone(Example 29),[1-(3,5-bis-trifluoromethyl-benzyl)-5-imidazol-1-yl-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-3-methyl-isoxazol-4-yl]-methanone(Example 97),[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-[4-(2-chloro-phenyl)-2-cyclopropyl-oxazol-5-yl]-methanone(Example 255),[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-[4-(2-chloro-phenyl)-2-cyclopropyl-oxazol-5-yl]-methanone(Example 254),[1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazol-4-yl]-[4-(2-chloro-phenyl)-1-methyl-1H-pyrazol-5-yl]-methanone(Example 246),[1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazol-4-yl]-[3-(2-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-yl]-methanone(Example 106),[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-[3-(2-chloro-phenyl)-5-hydroxy,ethyl-isoxazol-4-yl]-methanone (Example 64).

SCHEMES

The compounds disclosed herein can be made according to the followingschemes. The schemes, preparations, and examples should in no way beunderstood to be limiting in any way as to how the compounds may bemade.

The skilled artisan will appreciate that the introduction of certainsubstituents will create asymmetry in the compounds of Formula (I). Thepresent invention contemplates all stereoisomers, enantiomers, andmixtures of enantiomers, including racemates and diastereomers. It ispreferred that the compounds of the invention containing chiral centersare single enantiomers.

As the following schemes, preparations, and examples demonstrate, manyof the compounds of the present invention are not only selective NK-1receptor antagonists, but are also useful intermediates for thepreparation of additional compounds of Formula (I). It will berecognized by one of skill in the art that the individual steps in thefollowing schemes may be varied to provide the compounds of Formula (I).The particular order of steps required to produce the compounds ofFormula (I) is dependent upon the particular compound being synthesized,the starting compound, and the relative lability of the substitutedmoieties. Some substituents have been eliminated in the followingschemes for the sake of clarity and are not intended to limit theteaching of the schemes in any way.

In Scheme 1, Route 1, the triazole compounds of Formula (3a) are formedby reacting a beta keto ester of Formula (2), in which R^(x) is C₁–C₄alkyl or benzyl, with an azide of Formula (1). Such ring formations arewell known and appreciated in the art. See Savini et al., Farmaco (1994)49(5): 363–370; Martini et al., J. Pharm. Sci. (1988) 77(11): 977–980;Sun et al., Magn. Reson. Chem. (1998) 36(6): 459–460; Settimo et al.,Farmaco Ed. Sci. (1983) 38(10): 725–737; Olesen et al., J. Heterocycl.Chem. (1984) 21: 1603–1608; L'abbe et al., Bull. Soc. Chim. Belg. (1987)96(10): 823–824; Julino et al., J. Chem. Soc. Perkin Trans. 1 (1998) 10:1677–1684; Mamedov et al., Chem. Heterocycl. Compd. (Engl. Transl.)(1993) 29(5): 607–611; Wender et al., Tetrahedron Lett. (1987) 28(49):6125–6128; Freitas et al., J. Heterocycl. Chem. (1995) 32(2): 457–462;Cottrell et al., J. Heterocycl. Chem. (1991) 28(2): 301–304. The productof Formula (3) can be isolated and purified by techniques well known inthe art, such as precipitation, filtration, extraction, evaporation,trituration, chromatography, or recrystallization.

Azides of Formula (1) are commercially available or can be synthesizedfrom the corresponding halide or sulfonate ester derivatives by reactionwith an azide source, such as NaN₃, LiN₃, or tetrabutyl ammonium azide(Bu4NN₃), with NaN₃ being preferred, in a suitable solvent mixture suchas DMSO and water. Alternatively, azides of Formula (1) may be preparedfrom the corresponding alcohol derivative by reaction with hydrazoicacid, diphenylphosphoryl azide, or zinc azide, in the presence oftriphenylphosphine and diethyl- or diisopropyl-azodicarboxylate, in asolvent such as THF or toluene. See Scriven, E., Turbull, K., “Azides:Their Preparation and Synthetic Uses”, Chem Rev. 1988, 88, 351–368.

The skilled artisan will also appreciate that a malonate derivative ofFormula (2), in which R⁵ is an oxygen-linked substituent such as a C₁–C₄alkoxy, may be used in the reaction of step a, instead of a beta ketoester, to provide a triazole of Formula (3). The reaction of bothmalonates and beta keto esters with azides is well known and appreciatedin the art. See Benetti, S.; Romagnoli, R.; De Risi, C.; Zanirato, Z“Mastering β-Keto Esters,” Chem. Rev. 1995, 95, 1065–1114.

When dialkylmalonates are chosen as the starting reagent, R⁵ in theresulting product of Formula (3a) is a hydroxyl group. The hydroxylgroup may be readily converted to the corresponding halide. Examples ofreagents for this reaction include PCl₅, POCl₃, PBr₃, POBr₃, and thionylchloride, with PCl₅ as the preferred reagent. This type oftransformation is well known and appreciated in the art. See Buckle, D.R.; Rockell, C. J. M. J. Chem. Soc., Perkin I, 1982, 627–630.

In Route 2, compounds of Formula (5) may be prepared by exposing thefree base or the hydrochloride salt of compounds of Formula (4), whereinR⁵ is —NH₂, to a combination of a suitable base and an appropriatealkylating agent in a suitable solvent. Preferred bases include, but arenot limited to, sodium or potassium hydride, sodium or potassiumhexamethyldisilazide, or butyl lithium. Preferred alkylating agentsinclude alkyl halides or alkyl sulfonate esters. Preferred solventsinclude DMF, DME, or THF. This transformation is well-known in theliterature. (See for example: Kelly, J. L., J. Heterocyclic Chem., 1995,32, 1417.)

Compounds of Formula (5) may be dehydrated by treating the compound withtosyl chloride and pyridine to provide the nitrile containing compoundsof Formula (6). This transformation is well known to one skilled in theart and may be performed using other dehydrating agents. For a list ofalternate dehydrating conditions see: Larock, Comprehensive OrganicTransformations 2^(nd) ed., Wiley-VCH, New York, pp 1983–1985.

Compounds of Formula (6) in which R⁵ is —NH₂ may be readily converted toother R⁵ substituents of Formula (I) by reactions well known in the art.For examples, see Larock, Comprehensive Organic Transformations 2^(nd)ed., Wiley-VCH, New York, pp 678–679; Gajewski and Beck, J. HeterocyclicChem. (1987) 24: 243.

In step d, the nitrile functionality of compounds of Formula (6) isconverted to an ester-containing compound of Formula (3b). Thistranformation may be accomplished by treating the nitrile with an acid,such as hydrochloric acid or sulfuric acid, in a solution of an alcohol,such as methanol or ethanol, and water. Such transformations are wellknown in the art. For alternate conditions see: Larock, ComprehensiveOrganic Transformations 2^(nd) ed., Wiley-VCH, New York, pp 1986–1987.

Alternatively, compounds of Formula (3b) may be prepared by combining anamine of Formula (8) and a properly substituted bromo isocyanoacrylateof Formula (7), wherein R^(x) is a C₁–C₄ alkyl or benzyl, in thepresence of a base, preferably triethylamine, and an appropriatesolvent, preferably DMF. Compounds of Formula (7) may be preparedaccording to the literature. See: K. Nunami et al, J. Org. Chem. 1994,59, 7635–7642.

Step f depicts the reduction of the carboxylic acid ester of Formula(3), in which R^(x) is C₁–C₄ alkyl or benzyl, to give a substitutedmethanol of Formula (9). Such reduction steps are well known andappreciated in the art. See Larock, R. C., Comprehensive OrganicTransformations, 2^(nd) Ed., copyright 1999, John Wiley & Sons, pp1117–1120.

In one variation of step f, the carboxylic acid ester of Formula (3) maybe reduced by a suitable reducing agent, such as sodium borohydride,lithium aluminumhydride, lithium borohydride, or diisobutylaluminumhydride, with sodium borohydride being the preferred reducingagent. Such reductions are generally carried out in a solvent, such asMeOH, EtOH, iPrOH, THF, toluene, methylene chloride, or mixturesthereof. The preferred solvent is absolute ethanol. The product can beisolated and purified by techniques described above.

Oxidation of an alkyl-hydroxy group of Formula (9) to the correspondingaldehyde of Formula (10) is well known in the art. A representativeexample is shown in step g, in which the methanol of Formula (9) can beoxidized by reacting it with an appropriate oxidizing agent, such asmanganese oxide. Other oxidizing agents include pyridine sulfurtrioxidecomplex, 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H)-one(Dess-Martin reagent), pyridinium chlorochromate, pyridinium dichromate,and catalytic tetrapropylammonium perruthenate (TPAP) withN-methylmorpholine N-oxide (NMO) as a co-oxidant. The aldehydes ofFormula (10) can be isolated by techniques described above.

Hydrolysis of the carboxyl esters of Formula (3) to give thecorresponding carboxylic acids of Formula (11), as shown in step h, is awell-known reaction. See Larock, R. C., Comprehensive OrganicTransformations, 2^(nd) Ed., copyright 1999, John Wiley & Sons, pp1959–1968. For example, an appropriate ester of Formula (3) may bedissolved in a suitable solvent, such as methanol or dioxane and water,and treated with a suitable base, such as NaOH or LiOH, to give acompound of Formula (11).

The reaction of step i is well known to the skilled artisan. Acarboxylic acid, such as that of Formula (11), is coupled with anappropriate amine, under peptide coupling conditions, to provide aminesof Formula (12). Suitable peptide coupling reagents includeN,N′-carbonyldiimidazole (CDI), N,N′-dicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), and1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide (PEPC). Suitablecatalysts for the coupling reaction includeN,N-[dimethyl]-4-aminopyridine (DMAP). Such coupling reactions are wellknown and appreciated in the art. See Larock, R. C., ComprehensiveOrganic Transformations, 2^(nd) Ed., copyright 1999, John Wiley & Sons,pp 1941–1949.

Alternatively, a compound of Formula (11) may be converted to an acidchloride derivative, preferably by reaction with oxalyl chloride andDMF, and used to acylate an amine to give a compound of Formula (12).Such acylation reactions are well known and appreciated in the art. SeeLarock, R. C., Comprehensive Organic Transformations, 2^(nd) Ed.,copyright 1999, John Wiley & Sons, pp 1929–1930. The product can beisolated and purified by techniques described above.

One skilled in the art could also appreciate the formation of the amidesof Formula (12) by a direct conversion of the carboxyl ester of Formula(3) by the use of a trialkyl-aluminum reagent with an appropriate amineor by use of a magnesium amide, as depicted in step j.

Compounds of Formula (12) can further undergo a reduction (shown in stepk) by treatment with a suitable reducing agent, such asdiisobutylaluminum hydride, lithium aluminum hydride or a borane-methylsulfide complex to afford aldehydes of Formula (10). See Larock, R.,Comprehensive Organic Transformations, 2^(nd) ed. Wiley-VCH: New York,1999, pp 1269–1271.

Alkynyl-ketones of Formula (14) can be synthesized from the aldehydes ofFormula (10) or the N-methyl-N-methoxyamide derivatives of Formula (12).

Step 1 depicts the addition of an alkynyl anion to an aldehyde ofFormula (10) or a N-methyl-N-methoxyamide of Formula (12). The alkynylanion is generated by treating the appropriate alkyne with a suitablebase, such as methyl lithium, n-butyl lithium, tert-butyl lithium,lithium diisopropylamine, or preferably methyl or ethyl magnesiumbromide. When the aldehydes of Formula (10) are used, the hydroxyintermediate, Formula (13), can be oxidized to afford the ketone ofFormula (14). Such reactions are well known in the art. See Larock, R.C., Comprehensive Organic Transformations, 2^(nd) ed., Wiley-VCH: NewYork, 1999, pp 1234–1246. Alternatively, N-methyl-N-methoxyamidederivatives of Formula (12) are reacted with a suitable alkynyl anion toprovide compounds of Formula (14) directly.

Step n depicts the addition of an ethynyl anion reagent, such as ethynylmagnesium bromide, to an N-methyl-N-methoxyamide of Formula (12) to givethe vinylogous amide of Formula (15).

In step r, the compounds of Formula (21) are readily prepared bycross-coupling of a stannyl-triazole of Formula (19) and an acidchloride of Formula (20). This is accomplished by heating a mixture ofacyl chloride and stannane, in roughly molar equivalence, in thepresence of PdCl₂(PPh₃)₂ in degassed 1,4-dioxane at temperatures rangingfrom RT to 100° C. Other suitable catalysts include Pd(OAc)₂, Pd(PPh₃)₄,and Pd₂(dba)₃.CHCl₃. Alternative solvents include DMF, toluene, and THF.The compound of Formula (21) is concentrated and purified by techniquesknown in the art and described herein.

Stannyl triazoles of Formula (19) can be made from the reaction of anappropriate azide of Formula (1) with an appropriate stannyl-acetyleneof Formula (17). The reactants are combined in a suitable solvent, suchas benzene, chloroform, THF, or preferably toluene, and heated until thereaction is complete. The compound of Formula (19) is isolated andpurified by techniques known in the art and described above.

The stannyl-acetylenes of Formula (17) are readily available fromcommercial sources or can be prepared from compounds of Formula (16) oralternatively, from compounds of Formula (18). A compound of Formula(16) may be dissolved in an appropriate solvent, such as THF, followedby addition of bis(tributyl)tin oxide and an appropriate desilylatingagent, such as TBAF (tetrabutyl ammonium fluoride), or potassiumtrimethylsilanolate. Alternatively, the compound of Formula (17) is madeby dissolving an alkyne in an appropriate solvent, such as ether or THF,at −15 to −10° C. To this mixture is added nBuLi, followed bytributyltin chloride. The compound of Formula (17) may be used directlyor isolated and purified by techniques described above.

The formation of various stannyl acetylenes of Formula (17) is wellknown in the art. For example, see WO 00/51614; WO 00/01702; WO98/46228; Lambert et al., Journal of the Chemical Society, PerkinTransactions 2 (2001) 6: 964–974; Yamamoto et al., J. Chem. Soc., PerkinTrans.1 (1991) 12: 3253–7; Zhou et al., J. Chem. Soc., Perkin Trans. 1(1991) 11: 2827–30; Warner et al., J. Org. Chem. (1994), 59(19):5822–23; and Jacobi et al., Journal of the American Chemical Society(2000), 122(18): 4295–4303.

The silyl-acetylenes of Formula (16) are readily available fromcommercial sources. Alternatively, the skilled artisan will recognizethat compounds of Formula (16) may be prepared by reacting anappropriate aryl halide compound with trimethylsilyl acetylene to givethe silyl-alkyne. The reaction proceeds in the presence of copper iodideand a palladium catalyst, such asdichlorobis(triphenyl-phosphine)palladium (II). Other suitable catalystsinclude Pd(Ph₃)₄, Pd₂ dba₃.CHCl₃, or Pd(OAc)₂.

The skilled artisan will appreciate the cyclization of an alkyne ofFormula (14) with a nitrile oxide to afford compounds of Formula (I), asrepresented here by Formula (22), in which one of A² and A³ is nitrogen,and the other is oxygen. For examples of such cyclizations, see Joule,J. A.; Mills, K., Heterocyclic Chemistry, 4^(th) ed. Blackwell Science,Inc.:Malden, Mass., 2000, pp 442–448; Hussein, Ahmed Q.; El-Abadelah,Mustafa M.; Sabri, Wail S. Heterocycles from nitrile oxides I; J.Heterocycl. Chem. (1983), 20(2), 301–4.

For compounds of Formula (I) in which R⁵ is a halide, such as chloride,a substitution can be performed with an appropriate nucleophile such as,but not limited to, primary amines, secondary amines, alcohols or thiolsto further encompass compounds of the present invention. See March, J.,Advanced Organic Chemistry,. 1985, John Wiley and Sons, Inc., pp255–446.

Alternatively, [3+2] cyclization of a vinylogous amide of Formula (15)with a nitrile oxide under the above same cyclization conditions affordscompounds of Formula (22), in which one of A² and A³ is nitrogen, andthe other is oxygen, and in which R⁷ is hydrogen.

As shown in Scheme 4, Route 2, cyclization of compounds of Formula (14)can proceed to yield compounds of Formula (23). R^(x) represents a C₁–C₄alkane-diyl, unless otherwise specified. The skilled artisan willrecognize that compounds of Formula (23), in which Pg is a hydroxylprotecting group such as THP or trimethylsilane, may be deprotected, asshown in step v, to give a compound of Formula (24), which isencompassed in the scope of Formula (I). For example, the compound ofFormula (23) is dissolved in a suitable solvent, such as MeOH or EtOH,and treated with a suitable acid, such as p-TsOH.H₂O (para-toluenesulfonic acid) or CSA (camphor sulfonic acid). Alternatively, thealcohol may be liberated by treating with acetic acid in a mixture ofTHF and water. The product is isolated and purified as describedpreviously, or can be used without purification.

Additional transformations known to the skilled artisan or describedherein may be carried out to yield compounds of Formula (25–29), whichare all encompassed in the invention of Formula (I).

As shown in step w, alcohol-containing compounds of Formula (24), inwhich R^(x) is C₁–C₄ alkane-diyl, may be oxidized to give aldehydes ofFormula (25), wherein R^(x) is a bond or C₁–C₃ alkane-diyl. For example,the alcohol may be oxidized by reaction with a combination of DMSO,oxalyl chloride, and triethylamine in CH₂Cl₂. These and other oxidizingconditions are described in Larock, R. C., Comprehensive OrganicTransformations, 2^(nd) ed., Wiley-VCH: New York, 1999, pp 1234–1246.The skilled artisan will appreciate that aldehydes of Formula (25) mayalso be produced from the corresponding acetal by treatment with aqueousacidic conditions.

As shown in step x, aldehydes of Formula (25) may undergo furthertransformation to yield a compound of Formula (26), in which R^(x) is abond or C₁–C₃ alkane-diyl. The skilled artisan will appreciate that thistransformation may yield morpholino-substituted alkyl groups in additionto the —NR^(m)R^(n) groups depicted in step q. The amine is added to asolution of carbaldehyde in a solvent such as THF, or preferably1,2-dichloroethane, followed by addition of a suitable reducing agent,such as NaHB(OAc)₃ or NaBH₃CN. The compound is isolated and purifiedusing conditions well known to the skilled artisan and described above.

Alternatively, the compound of Formula (25) may undergo the reactiondepicted in step y to provide di-fluoro substituted compounds of Formula(27), in which R^(x) is a bond or C₁–C₃ alkane-diyl. In this reaction,(diethylamino)sulfur trifluoride or [bis(2-methoxyethyl)-amino]sulfurtrifluoride may be used as fluorinating agents. The fluorinating agentis added to dichloromethane, THF, or ether, and the reaction proceeds attemperatures ranging from RT to 50° C., for 1 to 6 hours. The compoundof Formula (27) is isolated and purified as described above.

As shown in step z, (diethylamino)sulfur trifluoride or[bis(2-methoxyethyl)-amino]sulfur trifluoride may be used asfluorinating agents to convert the alcohol of Formula (24) to thecompound of Formula (28). As in step y, dichloromethane, THF, or ethermay be used as solvents, and the reaction proceeds at temperaturesranging from −78° C. to 0° C. The reaction is stirred briefly and thenwarmed to RT. After 0.5 to 24 hours, the product may be isolated andpurified as described above.

For synthesis of amines of Formula (29), the reaction is carried out asshown in step aa. When R^(x) is —CH₂—, the methanol of Formula (24) iscombined with diphenyl phosphoryl azide and1,8-diazabicyclo[5.4.0]undec-7-ene in a suitable solvent, such asdichloromethane, ether, DMF, or preferably THF, and stirred overnight attemperatures ranging from RT to 80° C. When R^(x) is C₂–C₄ alkyl, thealcohol of Formula (24) is converted to a suitable leaving group, suchas chloro, bromo, or sulfonate ester, under standard conditions, whichis displaced by an azide source, such as NaN₃ or LiN₃. The crude productis dissolved in a solvent, such as THF, and triphenylphosphine is addedwith several drops of water. The reaction proceeds after stirring forseveral hours to overnight. The resulting amine of Formula (29) ispurified by techniques well known to the skilled artisan.

In Scheme 5, a compound of Formula (14) may be combined with theappropriate azide of Formula (30) to give keto-triazole compounds ofFormula (1), in which —A¹—A²-A³— is —NR⁸—N═N— or —N═N—NR⁸—. The azide ofFormula (30) is prepared in a similar manner as the azides of Formula(1). The reaction is carried out essentially as described in Scheme 3,step p, above. The skilled artisan will appreciate that the R⁸substituent may undergo transformations similar to those describedelsewhere to give alternatively-substituted compounds of Formula (I).

To synthesize the keto-pyrazole compounds of Formula (I), as shown instep bb, Compound (14) is dissolved in a solvent, such as toluene,benzene, or preferably THF/ether. A suitable diazoalkyl reagent,preferably trimethylsilyl diazomethane, is added. The reaction proceedsat temperatures ranging from RT to 80° C. for 24 to 72 hours to providea regioisomeric mixture of pyrazoles of Formula (I), in which —A¹—A²—A³—is —NR⁸—N═CR⁷—, —N—NR⁸—CR⁷—, —CR⁷═N—NR⁸—, or CR⁷—NR⁸—N—, wherein R⁷ ishydrogen or C₁–C₄ alkyl, and R⁸ is hydrogen. The mixture can beseparated by methods well known to the skilled artisan.

To synthesize the above compounds of Formula (I) in which R⁸ is C₁–C₄alkyl, the desired pyrazole is dissolved in a solvent, such as ether, orpreferably THF, and cooled under N₂. Temperatures may range from −20° C.to RT, with 0° C. preferred. To the mixture is added a base, such ast-BuLi, sec-BuLi, NaH, or preferably n-BuLi, with stirring for 1 hour,followed by addition of a suitable alkylating agent, such as an alkylhalide or alkyl sulfonate. Preferred alkylating agents includedimethylsulfate or iodomethane. The reaction is stirred overnight whilewarming to RT. The reaction is quenched with water and extracted withEtOAc. The desired product is isolated and purified by techniques wellknown to the skilled artisan.

In Scheme 7, the formation of compounds of Formula (37), which areencompassed in the description of Formula (I), are shown. Step cc iscarried out by addition of a sodium carboxylate salt of the compound ofFormula (31) to a solution of an alpha-halo acetophenone of Formula(32), in which X is halo, such as chloro or bromo. The reaction iscarried out in a suitable solvent, such as DMF. The reaction proceeds attemperatures ranging from RT to 50° C. to yield the compound of Formula(33). The desired compound is extracted, concentrated, and purified bymethods well known to the skilled artisan.

Oxazoles of Formula (34) may be prepared by cyclization of compounds ofFormula (33) with acetamide, as shown in step dd. The reaction isconveniently carried out in the presence of an acid such as BF₃.OEt₂.The mixture is warmed to 100–130° C. for several hours, then cooled toRT. Extraction, concentration, and purification of the compound ofFormula (34) is carried out by methods well known to the skilledartisan. The reaction may be carried out neat, or in a suitable solvent,such as toluene, diphenyl ether, or chlorobenzene. Formation of oxazolesis well known in the art. For example, see Pei et al., Synthesis (1998)1298–1304; Joule and Mills, “Heterocylic Chemistry” (4^(th) ed., 2000)Blackwell Science, Ltd: Malden, Mass.; Chapter 21.

As shown in step ee, compounds of Formula (35), in which R^(x) is a halosuch as bromo or iodo, can be prepared from compounds of Formula (34).Where R^(x) is bromo, freshly recrystallized N-Bromo-Succinimide (NBS)and (PhCO)₂O₂ are added to a solution of the compound of Formula (34) inCCl₄. The skilled artisan will recognize that AIBN may be used as aradical initiator. Alternatively, iodination of the oxazole may becarried out with N-Iodo-Succinimide (NIS) to make a compound of Formula(35) in which R^(x) is iodo.

In step ff, t-BuLi is added to a solution of the 5-bromo-oxazole ofFormula (35), at −78 to −40° C., in a suitable solvent, such as THF orether. To this solution is added a solution of an aldehyde of Formula(10) in THF or ether. The reaction is stirred at this temperature, andthen warmed to RT for 24 to 60 hours. The alcohol of Formula (36) isconcentrated and purified by techniques well known in the art.

Alternatively, in step ff, if the Grignard reagent of Formula (35) isused, Mg turnings and a small crystal of iodine are added to a solutionof the 5-bromo-oxazole of Formula (35) in a freshly distilled solvent,such as THF or ether. The mixture is stirred at reflux temperature, thencooled to RT. A solution of the aldehyde of Formula (10) in a suitablesolvent, such as THF or ether, is added to the Grignard solution, andthe solution is stirred for 1–4 hours. The alcohol of Formula (36) isextracted, concentrated, and purified by techniques well known in theart.

In step gg, the alcohol of Formula (36) may react in the presence of asuitable oxidizing agent, such as MnO₂, to give the keto-oxazole ofFormula (37). The reaction is conveniently carried out in a solvent suchas CH₂Cl₂. Other solvents, such as diethyl ether or toluene, may beused, and the reaction may be carried out at RT or heated. The oxidationreaction of step gg may also be carried out by other procedures wellknown to the skilled artisan, such as Dess-Martin periodinane, Swern, orPDC.

Ketones of Formula (37) may also be prepared directly from oxazoles ofFormula (35) by treatment with an activated amide of Formula (12). Inthis variant, the oxazole is converted to the organo-lithium ororganomagnesium bromide reagent as described above (step ff) and asolution of the amide of Formula (12) in a suitable solvent, such as THFor ether, is added. The resulting mixture is stirred for 4–60 hours atRT. The product of Formula (37) is isolated and purified as describedabove.

In Scheme 8, synthesis of compounds of Formula (40), which areencompassed in the description of Formula (I), is shown. The compound ofFormula (38) undergoes a reaction similar to that shown in Scheme 7, togive the alcohol of Formula (39) or the keto-imidazole of Formula (40).The alcohol of Formula (39) may be oxidized to give the compound ofFormula (40) by methods well known to the skilled artisan and describedabove.

In Scheme 9, compounds of Formula (41), which are included in theinvention of Formula (I), may be prepared by dissolving the propynone ofFormula (14) in chlorobenzene, followed by addition of alpha-pyrone.Additional pyrone is added to drive the reaction to completion. Thereaction is carried out at 110–160° C., preferably 130° C., for 24 to 72hours. The reaction may also be carried out with other solvents, such astoluene, bromobenzene, diphenylether, or xylene.

In Scheme 10, the compound of Formula (42) undergoes successiveoxidation reactions to give the compounds of Formula (43) and (44), asshown in step ii. Thiomorpholino compounds of Formula (42) aresynthesized by substitution of the corresponding halide, as recognizedin the art and described elsewhere. The compound of Formula (44) mayalso be synthesized directly from compounds of Formula (42), as shown instep jj. Each of the compounds of Formula (42), (43), and (44) isencompassed in the scope of compounds of Formula (I).

In step ii, aqueous hydrogen peroxide is added to a solution of thethiomorpholinyl substrate of Formula (42) in a suitable solvent such asEtOH, CH₂Cl₂, or preferably, MeOH. The reaction proceeds, with stirring,at 0 to 40° C. for 8 to 48 hours. The products of Formula (43) or (44)may be purified by methods well known to the skilled artisan anddescribed above.

Alternatively, the compound of Formula (44) may be synthesized directly,as shown in step jj, by reaction with 3-chloroperoxybenzoic acid indichloromethane. The reaction may also be carried out with MeOH or EtOHas the solvent. The reaction proceeds, with stirring, at 0 to 40° C. for1 to 3 hours. The product is purified by techniques well known in theart.

As shown in Scheme 11, compounds of Formula (I) in which D² is nitrogencan be synthesized by forming the triazole in the final step. The stepsdescribed here correspond to those for similar reactions describedabove. Compounds of Formula (45), in which R^(x) is hydrogen or C₁–C₄alkoxy, are synthesized from the corresponding alkyne, as describedpreviously.

In the synthesis of the triazole compounds of Formula (I), a compound ofFormula (49) is reacted with the appropriate azide, as describedelsewhere.

The alkynyl-ketones of Formula (49) can be synthesized essentially asdescribed in Scheme 2. Briefly, in step 1, an alkynyl anion is added toa compound of Formula (45) in which R^(x) is hydrogen, or to anN-methyl-N-methoxyamide of Formula (47). The alkynyl anion is generatedby treating the appropriate alkyne with a suitable base, such as methyllithium, n-butyl lithium, tert-butyl lithium, lithium diisopropylamine,or preferably methyl or ethyl magnesium bromide. When aldehydes ofFormula (45) are used, the hydroxy intermediate, Formula (48), can beoxidized to afford the ketone of Formula (49). Such reactions are wellknown in the art. See Larock, R. C., Comprehensive OrganicTransformations, 2^(nd) ed., Wiley-VCH: New York, 1999, pp 1234–1246.Alternatively, N-methyl-N-methoxyamide derivatives of Formula (47) arereacted with a suitable alkynyl anion to provide compounds of Formula(49) directly.

The N-methyl-N-methoxyamide derivatives of Formula (47) are synthesized,as described herein, from compounds of Formula (45) in which R^(x) isC₁–C₄ alkoxy. See also, Larock, R. C., Comprehensive OrganicTransformations, 2^(nd) Ed., 1999, John Wiley & Sons, pp 1941–1949;1959–1968.

Scheme 12 depicts the synthesis of compounds of Formula (54), which areused in the reaction of Scheme 13.

Alkynes of Formula (50) may be prepared from an aldehyde of Formula (10)through reaction with a diazo alkyl phosphonate, such as(1-diazo-2-oxo-propyl)-phosphonic acid dimethyl ester. The reaction iscarried out in an appropriate solvent, such as MeOH or EtOH, and a base,such as K₂CO₃. As shown in step nn, the compound of Formula (51), inwhich X is —CH(OH)—, can be made from alkynes of Formula (50) bydeprotonation with a suitable base, such as LDA, NaH, or BuLi, followedby treatment with an appropriate aldehyde. The alcohol of Formula (51)may be oxidized to give the corresponding methanone, in which X is—C(O)—, by techniques well known in the art and described above.

In step oo, the methanone compound of Formula (51) may be treated with asubstituted nitroalkyl compound and an isocyanate, such as1,4-phenyl-diisocyanate, in the presence of a suitable base such astriethylamine to give an isoxazole of Formula (52), in which R^(x) isC₁–C₂ alkane-diyl.

The skilled artisan will recognize that the hydroxyl group of Formula(52) can be oxidized, as shown in step pp, to give compounds of Formula(53), wherein R^(x) is a bond or methylene. The alcohol can be oxidizedby a number of different oxidizing reagents, for example, underDess-Martin periodinane oxidizing conditions or using combination ofDMSO and triethylamine with oxalyl chloride. Such oxidations are readilyaccomplished by methods well known in the art. (Larock, R. C.,Comprehensive Organic Transformations, 2^(nd) ed., Wiley-VCH: New York,1999, pp 1234–1246). The product of the reaction can be isolated andpurified using techniques well know in the art.

Alternatively, compounds of Formula (53) can be made by deprotection ofthe appropriate acetal. Such deprotections are readily accomplished bymethods well known in the art. (Protecting Groups in Organic Synthesis,Theodora Greene (Wiley-Interscience)).

Compounds of Formula (54) can be synthesized by reacting the appropriatealdehyde-containing compound of Formula (53) with ammonium acetate orhydrazine under acidic conditions such acetic acid. For example, whenR^(x) is methylene in the compound of Formula (53), reaction withammonium acetate provides compounds of Formula (54) in which A⁷ is CR⁷.When R^(x) is a bond, reaction with hydrazine provides compounds ofFormula (54) in which A⁷ is nitrogen.

Scheme 13 shows the formation of compounds of Formula (I), in which R⁴is a radical of Formula (IB), through a reduction of compounds ofFormula (54). Specifically, the bicyclic isoxazole is dissolved in asuitable solvent, such as acetonitrile. To the reaction, is addedmolybdenum hexacarbonyl and water. The skilled artisan will recognizethat the solution may be heated for the reaction to proceed. Thereduction reaction may optionally be carried out using H₂/Pt-C in apressure sealed vessel. The product of Formula (I) is purified bytechniques well known in the art, such as silica gel chromatography orrecrystallization. Such reactions have been described in the art. SeeNitta et al., J. Chem. Soc., Chem. Commun. (1982) 877.

PREPARATIONS General Preparation A

Combine the appropriate alkyl halide (1 eq) and sodium azide (3 eq) inDMSO/water (10:1, ca. 10 mL/g NaN₃) and stir for 2–12 h at RT.Non-benzylic alkyl halides may require heating to 50–80° C. tofacilitate the reaction. When the reaction is complete, add water andextract with ether. Wash the organic layer with water (2×) and brine.Dry the organic layer (Na₂SO₄), filter, and concentrate under reducedpressure. Generally, the resulting azide may be used without furtherpurification.

By the method of General Preparation A, the following compounds can beprepared and isolated.

Prep. # Product Physical Data 1 1-azidomethyl-3-trifluoromethoxy- TLCR_(f) = 0.70 (20% EtOAc/hexanes) benzene 22-azidomethyl-1,4-bis-trifluoromethyl- TLC R_(f) = 0.90 (20%EtOAc/hexanes) benzene 3 1-azidomethyl-3-fluoro-5- TLC R_(f) = 0.78 (20%EtOAc/hexanes) trifluoromethylbenzene 4 1-azidomethyl-5-fluoro-2- TLCR_(f) = 0.76 (20% EtOAc/hexanes) trifluoromethylbenzene 51-azidomethyl-2-fluoro-5- TLC R_(f) = 0.78 (20% EtOAc/hexanes)trifluoromethylbenzene 6 1-azidomethyl-3-trifluoromethyl- TLC R_(f) =0.70 (20% EtOAc/hexanes) benzene 7 4-azidomethyl-1-fluoro-2- TLC R_(f) =0.89 (20% EtOAc/hexanes) trifluoromethylbenzene 81-azidomethyl-3,5-dichlorobenzene TLC R_(f) = 0.57 (20:1 hex/EtOAc) ¹HNMR (CDCl₃, 250 MHz) δ 7.36 (m, 1H), 7.25 (s, 2H), 4.36 (s, 2H). 91-azidomethyl-3,5-dimethylbenzene TLC R_(f) = 0.68 (20:1 hex/EtOAc) ¹HNMR (CDCl₃, 250 MHz) δ 7.03 (s, 1H), 6.96 (s, 2H), 4.30 (s, 2H), 2.37(s, 6H). 10 1-azidomethyl-3,5-bis-trifluoromethyl- TLC R_(f) = 0.42(20:1 hex/EtOAc) benzene ¹H NMR (CDCl₃, 250 MHz) δ 7.95 (s, 1H), 7.82(s, 2H), 4.58 (s, 2H) IR: 2105 cm⁻¹ 11 2-Azidomethyl-[1,3]dioxolane ¹HNMR (300 MHz, CDCl₃): δ 5.12 (t, J = 3.5 Hz, 1H), 4.02 (m, 4H), 3.36 (d,J = 3.5 Hz, 2H). 12 2-Azido-1,1-dimethoxy-ethane ¹H NMR (300 MHz,CDCl₃): δ 4.57 (t, J = 5.8 Hz, 1H), 3.42 (s, 6H), 3.39 (d, J = 5.5 Hz,2H). 13 (2-Azido-ethoxy)-tert-butyl-dimethyl- ¹H NMR (300 MHz, CDCl₃): δ3.80 (t, J = 6.6 silane Hz, 2H), 3.31 (t, J = 6.6 Hz, 2H), 0.82 (s, 9H),0.00 (s, 6H); TLC R_(f) 0.67 (30% EtOAc/Hexane)

Preparation 14 (2-methoxy-5-trifluoromethoxy-phenyl)-methanol

Dissolve 2-methoxy-5-trifluoromethoxy-benzaldehyde (9.0 g, 40.9 mmol) inMeOH (100 mL) and treat with sodium borohydride (1.45 g, 38.3 mmol).Stir at RT for 1 h., then carefully quench with 1N HCl to pH 3.Concentrate, then extract the aqueous mixture with CH₂Cl₂ (3×100 mL).Combine the organic phases and wash with saturated NaHCO₃ (100 mL) andbrine (100 mL). Dry the organic layer, then filter, and concentrate.Purify the crude material by flash chromatography using a lineargradient of 100% hexanes to 40% EtOAc/hexanes to give(2-methoxy-5-trifluoromethoxy-phenyl)-methanol (6.86 g, 75%) as acolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.19 (m, 1H), 7.10 (dd, 1H,J=2.9, 8.8 Hz), 6.83 (d, 1H, J=8.8 Hz), 4.66 (d, 2H, J=6.4 Hz), 3.85 (s,3H), 2.21 (t, 1H, J=6.4 Hz).

Preparation 15 2-Azidomethyl-1-methoxy-4-trifluoromethoxy-benzene

Dissolve (2-methoxy-5-trifluoromethoxy-phenyl)-methanol (4.49 g, 20.2mmol) in DMF (40 mL) and treat with thionyl chloride (1.65 g, 22.6mmol). Stir at RT for 2 h, then treat with potassium carbonate (5.57 g,40.3 mmol), sodium azide (2.35 g, 36.1 mmol), and DMSO (40 mL). Stir theresulting mixture at RT overnight, then pour into water (100 mL) andextract with ether (3×100 mL). Combine the organic phases and wash withwater (2×100 mL) and brine (100 mL). Dry the organic layer (MgSO₄),filter, and concentrate to give the title compound (4.77 g, 96%) as acolorless oil that may be used without further purification. ¹H NMR (400MHz, CDCl₃) δ 7.14 (m, 2H), 6.87 (m, 1H), 4.34 (s, 2H), 3.85 (s, 3H).

Preparation 16 3-Oxo-3-pyrimidin-5-yl-propionic acid methyl ester

Add a 25 wt % solution of sodium methoxide in methanol (4.5 mL, 19.8mmol) to toluene (40 mL) and heat to 85° C. under N₂. Dissolvepyrimidine-5-carboxylic acid ethyl ester (2.0 g, 13.2 mmol) in EtOAc(2.1 mL) and add dropwise to the toluene solution. Heat the reactionmixture for 1 h, then add a suspension of sodium methoxide (715 mg, 13.2mmol) in EtOAc (15 mL) dropwise. Heat the reaction mixture at 85° C.overnight, then cool to RT and pour into a solution of glacial aceticacid (12 mL) and water. (50 mL). After stirring for 1 h at RT, extractwith EtOAc (3×100 mL). Wash the organic phase with brine (200 mL), dryover sodium sulfate, filter, and concentrate under reduced pressure togive the title compound as a mixture of tautomers: ¹H NMR (300 MHz,CDCl₃) enol form δ 12.43 (s, 1H), 9.26 (s, 1H), 9.10 (s, 2H), 5.76 (s,1H), 3.86 (s, 3H); keto form δ 9.42 (s, 1H), 9.30 (s, 2H), 4.06 (s, 3H),3.74 (s, 2H).

Preparation 17 3-Oxo-3-pyrazin-2-yl-propionic acid methyl ester

Dissolve NaOMe (1.5 eq) in toluene and heat to 90° C. Add a solution of2-pyrazine methylester (1.0 eq) and EtOAc (2.0 eq) in toluene dropwiseand heat at 90° C. After 20 h, concentrate the mixture in vacuo. Slurryin excess EtOAc and reflux 20 h. Cool to RT, then add water and extractwith EtOAc. Dry (Na₂SO₄), filter and concentrate in vacuo to give thetitle compound. TLC R_(f)=0.58 (1:1 EtOAc/hexanes).

Preparation 181-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazole-4-carboxylicacid ethyl ester

Treat a solution of ethyl isonicotinoylacetate (2.52 g, 13.0 mmol) and3,5-bis-trifluourobenzyl azide (3.54 g, 13.1 mmol) in DMSO (20 mL) withmilled K₂CO₃ (5.72 g, 41.4 mmol). Warm the mixture to 40° C. and stirfor 18 h, then dilute with H₂O and treat with 1N HCl until mixturereaches pH 7. Extract the mixture with EtOAc (2×50 mL). Combine theorganic phases and wash with H₂O (2×50 mL) and brine (50 mL), then dry,filter, and concentrate organic layer. Triturate crude material withhexanes, then recrystallize solid from 40% EtOAc/hexanes to give thetitle compound (2.80 g, 48%). MS (EI+) 445.2 (M+H); ¹H NMR (400 MHz,CDCl₃): δ 8.74 (dd, 2H, J=1.5, 4.4 Hz), 7.80 (s, 1H), 7.45 (s, 2H), 7.13(dd, 2H, J=2.0, 4.4 Hz), 5.56 (s, 2H), 4.27 (q, 2H, J=7.3 Hz), 1.28 (t,3H, J=7.3 Hz). Analytical (C₁₉H₁₄F₆N₄O₂): Calculated C, 51.36; H, 3.18;N, 12.61. Found C, 51.35; H, 3.21; N, 12.52.

By a method analogous to Preparation 18, the following compounds may beprepared and isolated.

Prep. # Product Physical Data 19 1-(3,5-bis-trifluoromethyl-benzyl)-5-MS (ES) 382.1 (M+1), MS (ES−) 380.0 (M−1).methyl-1H-[1,2,3]triazole-4-carboxylic ¹H NMR (400 MHz, CDCl₃) δ 7.86(s, 1H), acid ethyl ester 7.64 (s, 2H), 5.62 (s, 2H), 4.42 (q, 2H, J =7.4 Hz), 2.50 (s, 3H), 1.41 (t, 3H, J = 7.4 Hz). 201-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 431.1 (M+H). ¹H NMR (400MHz, pyridin-3-yl-1H-[1,2,3]triazole-4- CDCl₃): δ 8.76 (s, 1H), 8.49 (s,1H), carboxylic acid ethyl ester 7.79 (s, 1H), 7.51 (m, 1H), 7.41 (s,2H), 7.40 (m, 1H), 5.59 (s, 2H), 3.83 (s, 3H). 211-(3,5-bis-trifluoromethyl-benzyl)-5- R_(f) = 0.42 (2:1 hexanes/EtOAc);MS (ES): phenyl-1H-[1,2,3]triazole-4-carboxylic 444.1 (M+1); ¹H NMR(CDCl₃, 250 MHz) acid ethyl ester δ 7.82 (s, 1H), 7.4–7.6 (m, 5H), 7.20(m, 2H), 5.58 (s, 2H), 4.35 (q, 2H), 1.27 (t, 3H). 221-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 431.29 (M+1);pyrazin-2-yl-1H-[1,2,3]triazole-4- TLC R_(f) = 0.29 (1:1 EtOAc/hexanes)carboxylic acid methyl ester 23 1-(3,5-bis-trifluoromethyl-benzyl)-5- ¹HNMR (300 MHz, CDCl₃) δ 9.34 (s, pyrimidin-5-yl-1H-[1,2,3]triazole-4-1H), 8.62 (s, 2H), 7.82 (s, 1H), 7.48 (s, carboxylic acid methyl ester2H), 5.63 (s, 2H), 3.91 (s, 3H) 241-(3,5-dichloro-benzyl)-5-pyridin-4-yl- MS (ES) 377.0, 379.0 (M+1); TLCR_(f) = 0.50 (7% 1H-[1,2,3]triazole-4- MeOH/CH₂Cl₂). carboxylic acidethyl ester 25 1-(3,5-dichloro-benzyl)-5-pyridin-3-yl- MS (ES) 363.0,365.0 (M+1)⁺; R_(f) = 0.38 (6.7% 1H-[1,2,3]triazole-4-carboxylic acidMeOH/CH₂Cl₂). methyl ester 26 5-pyridin-3-yl-1-(3-trifluoromethyl- MS(ES) 363.2, 364.2 (M+1)⁺. benzyl)-1H-[1,2,3]triazole-4- carboxylic acidmethyl ester 27 5-pyridin-3-yl-1-(4-trifluoromethyl- MS (ES) 363.2,364.2 (M+1)⁺; R_(f) = 0.28 (6.7% benzyl)-1H-[1,2,3]triazole-4-MeOH/CH₂Cl₂). carboxylic acid methyl ester 281-(2,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 431.2, 432.2 (M+1)⁺.pyridin-3-yl-1H-[1,2,3]triazole-4- carboxylic acid methyl ester 291-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES+) 431.0 (M+1)⁺, MS (ES−)429.0 pyridin-3-yl-1H-[1,2,3]triazole-4- (M−1)⁻; ¹H NMR (400 MHz, CDCl₃)δ carboxylic acid methyl ester 8.70 (dd, 1H, J = 1.8, 4.9 Hz), 8.49 (d,1H, J = 2.3 Hz), 7.91 (s, 1H), 7.51 (dt, 1H, J = 1.9, 7.8 Hz), 7.41 (s,2H), 7.40 (m, 1H), 5.59 (s, 2H), 3.84 (s, 3H). 301-(3,4-difluoro-benzyl)-5-pyridin-3-yl- MS (ES) 331.1, 332.2 (M⁺+1);R_(f) = 0.19 (6.7% 1H-[1,2,3]triazol-4-carboxylic acid MeOH/CH₂Cl₂)methyl ester

Preparation 311-(3,5-bis-trifluoromethyl-benzyl)-5-hydroxy-1H-[1,2,3]triazole-4-carboxylicacid ethyl ester

Combine a solution of sodium ethoxide (5.5 mL, 21 wt % in ethanol) anddiethyl malonate (2.50 mL, 16.5 mmol) in ethanol (26 mL) with a solutionof 1-azidomethyl-3,5-bis-trifluoromethyl-benzene (4.40 g, 16.3 mmol) inethanol (6 mL) and heat to 80° C. After 7 h, cool to RT and concentratethe mixture in vacuo. Dissolve the viscous oil in H₂O (20 mL) and addaqueous 1N HCl until the solution reaches pH 2–3. Collect the whiteprecipitate by filtration and dry under reduced pressure to give thetitle compound. MS (ES) 384.0 (M+H)⁺, MS (ES−) 382.1 (M−H); ¹H NMR (400MHz, CDCl₃) δ 8.05 (s, 1H), 7.92 (s, 2H), 5.41 (s, 2H), 4.15 (q, 2H,J=7.3 Hz), 1.22 (t, 3H, J=7.3 Hz).

Preparation 321-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carboxylicacid ethyl ester

Combine PCl₅ (5.73 g, 27.5 mmol) with a solution of1-(3,5-bis-trifluoromethyl-benzyl)-5-hydroxy-1H-[1,2,3]triazole-4-carboxylicacid ethyl ester (5.30 g, 13.8 mmol) in toluene (150 mL) and heat to 50°C. After 2 h, cool to RT, concentrate solution and dissolve crudematerial in ether (100 mL). Wash the organic solution with saturatedNaHCO₃ (2×100 mL) and brine (100 mL), dry, filter, and concentrate.Purify the crude material by passing through a short plug of silica gelusing a linear gradient of 50% to 80% EtOAc/hexanes, then recrystallizefrom 1:1 diethyl ether:petroleum ether (150 mL). MS (ES) 402.0 (M+H)⁺;¹H NMR (400 MHz, CDCl₃) δ 7.88 (s, 1H), 7.76 (s, 2H), 5.67 (s, 2H), 4.43(q, 2H, J=7.0 Hz), 1.40 (t, 3H, J=7.0 Hz).

Preparation 331-(3,5-Dichloro-benzyl)-5-hydroxy-1H-[1,2,3]triazole-4-carboxylic acidethyl ester

Combine diethylmalonate (1.91 g, 11.9 mmol), 3,5-dichlorobenzylazide(2.40 mL, 11.9 mmol), and potassuim carbonate (4.94 g, 35.8 mmol) inDMSO (15 mL) and heat the mixture 8 h at 50° C. Dilute the cooledmixture with water, adjust pH to 5–6 with aqueous HCl, and extract withCH₂Cl₂. Wash the combined extracts with water, dry over Na₂SO₄, filter,and concentrate in vacuo. Chromatography of the resulting residue oversilica gel using a CH₂Cl₂/MeOH gradient yields 3.28 g of the titlecompound as an oil. MS(ES) 316.0, 318.0 (M+1)⁺.

Preparation 345-chloro-1-(3,5-dichloro-benzyl)-1H-[1,2,3]triazole-4-carboxylic acidethyl ester

Combine1-(3,5-dichloro-benzyl)-5-hydroxy-1H-[1,2,3]triazole-4-carboxylic acidethyl ester (1 eq) with PCl₅ (2 eq) in toluene and heat at 40–50° C.until reaction is complete. Concentrate the mixture, treat with aqueousNaHCO₃, and extract with Et₂O. Dry the combined extracts over Na₂SO₄,concentrate, and purify by chromatography on silica gel. MS (ES) 334.0,336.0 (M+1)⁺.

General Preparation B

Add a solution of LiOH.H₂O (10 eq) in water to a solution of theappropriate ester (1 eq) in dioxane and stir overnight. Acidify to a pHof 1–2 with 5N HCl solution and collect the precipitate by filtration.Dry the material in vacuo to afford the desired product.

By the method of General Preparation B, the following compounds may beprepared.

Prep. # Product Physical Data 35 1-(3,5-bis-trifluoromethyl-benzyl)-5-MS (ES) 372 (M⁺−1); ¹H NMR (400 MHz,chloro-1H-[1,2,3]triazole-4-carboxylic DMSO): 5.89 (s, 2H); 8.03 (s,acid 2H); 8.15 (s, 1H) 36 1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES)415 (M⁺−1); ¹H NMR (400 MHz, pyridin-4-yl-1H-[1,2,3]triazole-4- DMSO):5.76 (s, 2H); 7.43 (d, 2H, carboxylic acid J = 5.9 Hz); 7.70 (s, 2H);8.04 (s, 1H); 8.66 (d, 2H, J = 5.9 Hz) 371-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 418.1 (M+1)pyrazin-2-yl-1H-[1,2,3]triazole-4- carboxylic acid 381-(3,5-dichloro-benzyl)-5-pyridin-4-yl- MS (ES) 349.0, 351.0 (M+1)1H-[1,2,3]triazole-4- carboxylic acid 395-chloro-1-(3,5-dichloro-benzyl)-1H- MS (FAB) 305.9 M⁺; TLC R_(f) = 0.05(7% [1,2,3]triazole-4-carboxylic acid MeOH/CH₂Cl₂) 401-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES−) 415.1 (M−H); ¹H NMR (400pyridin-3-yl-1H-[1,2,3]triazole-4- MHz, DMSO-d₆): δ 13.05 (br s, 1H),carboxylic acid 8.66 (m, 1H), 8.56 (d, 1H, J = 1.5 Hz), 8.05 (s, 1H),7.85 (dt, 1H, J = 2.0, 7.8 Hz), 7.71 (s, 2H), 7.48 (dd, 1H, J = 4.9, 7.8Hz), 5.79 (s, 2H). 41 1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES−)352.1 (M−H); ¹H NMR (400 methyl-1H-[1,2,3]triazole-4-carboxylic MHz,DMSO-d6) δ 7.31 (s, 1H), 7.14 (s, acid 2H), 5.00 (s, 2H), 2.50 (s, 3H).42 1-(3,5-bis-trifluoromethyl-benzyl)-5- R_(f) = 0.40 (2:1 CHCl₃/MeOH);MS (ES): phenyl-1H-[1,2,3]triazole-4-carboxylic 416.1 (M+1) acid 431-(3,5-bis-trifluoromethyl-benzyl)-5- ¹H NMR (300 MHz, CDCl₃) δ 9.27 (s,pyrimidin-5-yl-1H-[1,2,3]triazole-4- 1H), 8.64 (s, 2H), 7.84 (s, 1H),7.50 (s, carboxylic acid 2H), 5.69 (s, 2H) 441-(3,5-dichloro-benzyl)-5-pyridin-3-yl- MS (ES) 349.0, 351.0 (M+1)1H-[1,2,3]triazole-4-carboxylic acid 45 5-pyridin-3-yl-1(3-trifluoromethyl- MS (ES) 349.1, 350.2 (M+1)benzyl)-1H-[1,2,3]triazole-4-carboxylic acid 46 5-pyridin-3-yl-1(4-trifluoromethyl- MS (ES) 349.2, 350.2 (M+1)benzyl)-1H-[1,2,3]triazole-4-carboxylic acid 471-(2,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 417.2 (M+1)pyridin-3-yl-1H-[1,2,3]triazole-4- carboxylic acid 481-(2-methoxy-5-trifluoromethoxy- MS (ES+) 395.2 (M+1)⁺.benzyl)-5-pyridin-3-yl-1H- ¹H NMR (400 MHz, DMSO-δ₆) δ 12.99 (br[1,2,3]triazole-4-carboxylic acid s, 1H), 8.66 (d, 1H, J = 3.9 Hz), 8.58(s, 1H), 7.88 (dt, 1H, J = 2.0, 7.8 Hz), 7.51 (dd, 1H, J = 4.9, 7.8 Hz),7.29 (dd, 1H, J = 2.4, 8.8 Hz), 7.01 (m, 2H), 5.46 (s, 2H), 3.58 (s,3H). 49 1-(3,4-difluoro-benzyl)-5-pyridin-3-yl- MS (ES) 317.1, 318.2(M⁺+1) 1H-[1,2,3]triazol-4-carboxylic acid

General Preparation C

Add N,O-dimethyl-hydroxylamine (1.3 eq), EDCI (1.3 eq), and DMAP(0.6–1.3 eq) to a solution of the appropriate carboxylic acid (1 eq) inCH₂Cl₂ (0.3 M). Stir the solution at RT for 5–24 h, then dilute withCH₂Cl₂ and wash with water, saturated NaHCO₃, and brine. Dry, filter,and concentrate the organic solution and purify the crude material byflash chromatography or by recrystallization.

By the method of General Preparation C, the following compounds may beprepared and isolated.

Prep. # Product Physical Data 50 1-(3,5-bis-trifluoromethyl-benzyl)-5-MS (ES) 460.1 (M−H), MS (ES⁻) 458.1 pyridin-3-yl-1H-[1,2,3]triazole-4-(M−H); ¹H NMR (400 MHz, CDCl₃) δ carboxylic acid methoxy-N-methyl- 8.72(s, 1H), 8.50 (s, 1H), 7.80 (s, 1H), amide 7.58 (d, 1H, J = 7.6 Hz),7.43 (s, 2H), 7.36 (dd, 1H, J = 4.8, 7.7 Hz), 5.57 (s, 2H), 3.86 (s,3H), 3.33 (br s, 3H). 51 1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES)397.1 (M+H), MS (ES−) 395.1 methyl-1H-[1,2,3]triazole-4-carboxylic(M−H); ¹H NMR (400 MHz, CDCl₃) δ acid methoxy-N-methyl-amide 7.86 (s,1H), 7.67 (s, 2H), 5.60 (s, 2H), 3.89 (s, 3H), 3.45 (br s, 3H), 2.46 (s,3H) 52 1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 461.2 (M+1); TLCR_(f) = 0.47 (5% pyrazin-2-yl-1H-[1,2,3]triazole-4- MeOH/CHCl₃)carboxylic acid methoxy-N-methyl- amide 531-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 417.0 (M+H); ¹H NMR (400MHz, chloro-1H-[1,2,3]triazole-4-carboxylic CDCl₃) δ 7.88 (s, 1H), 7.78(s, acid methoxy-N-methyl-amide 2H), 5.64 (s, 2H), 3.86 (s, 3H), 3.40(br s, 3H). 54 1-(3,5-bis-trifluoromethyl-benzyl)-5- ¹H NMR (300 MHz,CDCl₃) δ 9.30 (s, pyrimidin-5-yl-1H-[1,2,3]triazole-4- 1H), 8.63 (s,2H), 7.84 (s, 1H), 7.47 (s, carboxylic acid methoxy-N-methyl- 2H), 5.58(s, 2H), 3.90 (s, 3H), 3.38 (br amide s, 3H). 551-(3,5-bis-trifluoromethyl-benzyl)-5- ¹H NMR (500 MHz, CDCl₃) δ 8.75 (d,J = 5.7 pyridin-4-yl-1H-[1,2,3]triazole-4- Hz, 2H), 7.85 (s, 1H), 7.50(s, 2H), carboxylic acid methoxy-N-methyl- 7.21 (d, J = 5.7 Hz, 2H),5.57 (s, 2H), amide 3.87 (s, 3H), 3.32 (s, 3H); MS (m/e): 460.1 (M+H⁺).56 1-(3,5-bis-trifluoromethyl-benzyl)-5- ¹H NMR (500 MHz, CDCl₃) δ 7.79(s, 1H), phenyl-1H-[1,2,3]triazole-4-carboxylic 7.52–7.44 (m, 5H),7.24–7.22 (m, 2H), acid methoxy-N-methyl amide 5.55 (s, 2H), 3.83 (s,3H), 3.33 (s, 3H). MS (m/e): 459.1 (M+H⁺). 571-(3,5-dichloro-benzyl)-5-pyridin-4-yl- MS (ES) 392.22 (M+1)1H-[1,2,3]triazole-4-carboxylic acid methoxy-N-methyl-amide 581-(3,5-dichloro-benzyl)-5-pyridin-3-yl- MS (ES) 392.1, 394.0 (M+1)⁺.R_(f) = 0.30 (6.7% 1H-[1,2,3]triazole-4-carboxylic acid MeOH/CH₂Cl₂).methoxy-N-methyl-amide 59 5-pyridin-3-yl-1 (3-trifluoromethyl- MS (ES)392.2, 393.2 (M+1)⁺. R_(f) = 0.31 (6.7%benzyl)-1H-[1,2,3]triazole-4-carboxylic MeOH/CH₂Cl₂). acidmethoxy-N-methyl-amide 60 5-pyridin-3-yl-1 (4-trifluoromethyl- MS (ES)392.2, 393.3 (M+1)⁺. R_(f) = 0.19 (6.7%benzyl)-1H-[1,2,3]triazole-4-carboxylic MeOH/CH₂Cl₂). acidmethoxy-N-methyl-amide 61 1-(2,5-bis-trifluoromethyl-benzyl)-5- MS (ES)460.2, 461.2 (M+1)⁺. R_(f) = 0.22 (6.7%pyridin-3-yl-1H-[1,2,3]triazole-4- MeOH/CH₂Cl₂). carboxylic acidmethoxy-N-methyl- amide 62 1-(2-methoxy-5-trifluoromethoxy- MS (ES+)438.2 (M+1)⁺. ¹H NMR (400 MHz, benzyl)-5-pyridin-3-yl-1H- CDCl₃) δ 8.65(dd, 1H, J = 2.0, [1,2,3]triazole-4-carboxylic acid 4.9 Hz), 8.48 (d,1H, J = 1.5 Hz), 7.66 (dt, methoxy-N-methyl-amide 1H, J = 2.0, 8.3 Hz),7.34 (dd, 1H, J = 4.9, 8.3 Hz), 7.11 (dd, 1H, J = 2.0, 8.8 Hz), 6.82 (d,1H, J = 2.4 Hz), 6.75 (d, 1H, J = 8.8 Hz), 5.45 (s, 2H), 3.84 (s, 3H),3.63 (s, 3H), 3.34 (br s, 3H). 631-(3,4-difluoro-benzyl)-5-pyridin-3-yl- MS (ES) 360.2, 361.2 (M⁺+1);1H-[1,2,3]triazol-4-carboxylic acid R_(f) = 0.07 (50% EtOAc/CH₂Cl₂)methoxy-N-methyl-amide

Preparation 64[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-methanol

Dissolve1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazole-4-carboxylicacid methyl ester (10.0 g) in MeOH (110 mL). Add NaBH₄ (2.64 g, 3 eq)and warm to reflux overnight (70° C.). Cool to RT and slowly pour into aseparatory funnel containing an equal volume of water; extract withCH₂Cl₂. Dry the organic layer, concentrate, and recrystallize fromEtOAc/Hexanes to give 7.0 g (75%) of the title compound. MS (ES) 403.2(M+1); ¹H NMR: (400 MHz, CD₃OD) δ: 8.65 (dd, J=5.2, 1.6 Hz, 1H)8.53–8.52 (m, 1H), 7.89 (s, 1H), 7.86–7.83 (m, 1H), 7.60 (s, 2H),7.56–7.53 (m, 1H), 5.83 (s, 2H), 4.59 (s, 2H).

Preparation 651-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carbaldehyde

Add a solution of LiBH₄ (65 mL, 2M in THF) to a solution of1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carboxylicacid ethyl ester (15.0 g, 37.3 mmol) in THF (150 mL) at 0° C. Afteraddition is complete, stir solution at RT for 6 h, then cool again to 0°C. Carefully quench with slow addition of 5N HCl (50 mL). Stir at RT for30 min., then neutralize with 5N NaOH. Dilute mixture with water (100mL) and extract with EtOAc (2×50 mL). Combine the organic phases andwash with water (100 mL), and brine (100 mL) then dry, filter, andconcentrate to give the alcohol, which can be used in the next reactionwithout further purification.

Add Dess-Martin periodinane (19.0 g, 44.8 mmol) to a 0° C. solution ofthe above alcohol in CH₂Cl₂ (100 mL). Stir solution at 0° C. for 15min., then at RT for 2 h. Add additional Dess-Martin periodinane (1.7 g,4.0 mmol) and stir at RT for 1 h. Pour solution into cold 5N NaOH (70mL) and extract with ether (3×150 mL). Combine the organic phases andwash with 1N NaOH (100 mL), water (100 mL), and brine (100 mL), thendry, filter, and concentrate. Purify the crude material by flashchromatography to give the title compound. MS (ES) 358.1(M+H). ¹H NMR(400 MHz, CDCl₃) δ 10.13 (s, 1H), 7.90 (s, 1H), 7.76 (s, 2H), 5.67 (s,2H).

By a method similar to Preparation 65, the following compound may beprepared.

Prep. # Product Physical Data 66 1-(3,5-bis-trifluoro- MS (ES) 401.1(M+1). ¹H NMR (300 methyl-benzyl)-5- MHz, CDCl₃): δ 10.14 (s, 1H), 8.75(d, pyridin-4-yl-1H- J = 5.7 Hz, 2H), 7.80 (s, 1H), 7.47 (s,[1,2,3]triazole- 2H), 7.13 (dd, J = 4.0, 1.7 Hz, 2H), 5.554-carbaldehyde (s, 2H).

Preparation 671-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carbaldehyde

Add sodium borohydride (1.70 g, 0.045 mol) to a solution of1-(3,5-bis-trifluoromethylbenzyl)-5-phenyl-1H-[1,2,3]triazole-4-carboxylicacid ethyl ester (5.0 g, 0.011 mol) in EtOH (70 mL) and heat the mixtureto reflux. After 2 h, cool to RT and add the reaction mixture to 0.5 NHCl (200 mL) and methylene chloride (200 mL). Separate the layers andextract the aqueous layer with methylene chloride (50 mL). Dry thecombined organic layers over MgSO₄, filter, and concentrate to give[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-methanol.

Dissolve the crude[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-methanol(3.90 g, 0.0097 mol) in DMSO (30 mL) and add N,N-diispropylethylamine(6.77 mL, 0.039 mol). To this solution add sulfur trioxide pyridinecomplex (3.09 g, 0.019 mol) in DMSO (30 mL) and stir at RT. After 2 h.,add the reaction mixture to EtOAc (150 mL) and 0.5 N HCl (200 mL), andseparate the layers. Extract the aqueous layer with EtOAc (50 mL).Combine the organic layers and wash with saturated, aqueous sodiumbicarbonate (100 mL) and 1.0 N HCl (100 mL). Dry the organic layer overMgSO₄, filter, and concentrate to give the title compound. ¹H NMR (500MHz, DMSO) δ 9.91 (s, 1H), 8.02 (s, 1H), 7.69 (s, 2H), 7.55–7.49 (m,5H), 5.86 (s, 2H); MS (m/e): 400 (M⁺+1).

Preparation 681-[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazol-4-yl]-3-(2-chloro-2-yn-1-ol

Dissolve 1-chloro-2-ethynyl-benzene (22.1 g, 162 mmol) in THF (300 mL)and slowly add methyl magnesium bromide (50 mL, 3.0 M in ether). Stirthe solution at RT for 40 min., then add a solution of1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carbaldehyde(29.6 g, 82.8 mmol) in THF (160 ml). Stir the resulting solution at RTfor 2 h, then pour into cold water (500 mL) and 1N HCl (150 mL) andextract with EtOAc (3×200 mL). Combine the organic phases and wash withsaturated NaHCO₃ (200 mL) and brine (200 mL) then dry (MgSO₄), filter,and concentrate. Purify the crude material by triturating with 30%ether/hexanes to give the title compound. MS (ES) 494.0 (M+1), MS (ES−)492.0 (M−1); ¹H NMR (400 MHz, CDCl₃) δ 7.87 (s, 1H), 7.79 (s, 2H), 7.47(dd, 1H, J=1.9, 7.3 Hz), 7.37 (dd, 1H, J=1.4, 7.9 Hz), 7.25 (dt, 1H,J=2.0, 7.3 Hz), 7.19 (dt, 1H, J=1.5, 7.3 Hz), 5.92 (d, 1H, J=6.7 Hz),5.62 (s, 2H), 2.79 (d, 1H, J=6.4 Hz).

By a method similar to Preparation 68, using the appropriate aldehydeand alkyne, the following compounds may be prepared and isolated.

Prep. # Product Physical Data 691-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 536.0 (M+1); ¹H NMR(300 phenyl-1H-[1,2,3]triazol-4-yl]-3-(2- MHz, CDCl₃): δ 7.82 (s, 1H),7.56–7.12 chloro-phenyl)-prop-2-yn-1-ol (m, 11 H), 5.85 (s, 1H), 5.59(s, 2H). 70 1-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 502.2(M+1), TLC R_(f) 0.29 (50% phenyl-1H-[1,2,3]triazol-4-yl]-3-phenyl-EtOAc/Hexane) prop-2-yn-1-ol 71 1-[1-(3,5-bis-trifluoromethyl-benzyl)-5-MS (ES) 520.2 (M+1), TLC R_(f) 0.39 (50%phenyl-1H-[1,2,3]triazol-4-yl]-3-(4- EtOAc/Hexane)fluoro-phenyl)-prop-2-yn-1-ol 721-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 570.1 (M+1), TLC R_(f)0.36 (50% phenyl-1H-[1,2,3]triazol-4-yl]-3-(3- EtOAc/Hexane)trifluoromethyl-phenyl)-prop-2-yn-1-ol 731-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 520.1 (M+1), TLC R_(f)0.34 (50% phenyl-1H-[1,2,3]triazol-4-yl]-3-(2- EtOAc/Hexane)fluoro-phenyl)-prop-2-yn-1-ol 741-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 528.1 (M+1); TLC (50%Et₂O chloro-1H-[1,2,3]triazol-4-yl]-4-(tert- in hexanes): R_(f) = 0.2.butyl-dimethyl-silanyloxy)-but-2-yn-1-ol 751-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 570.1 (M+1); TLC (50%Et₂O phenyl-1H-[1,2,3]triazol-4-yl]-4-(tert- in hexanes): R_(f) = 0.1.butyl-dimethyl-silanyloxy)-but-2-yn-1-ol 761-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 542.0 (M⁺+1); TLC (50%Et₂O chloro-1H-[1,2,3]triazol-4-yl]-5-(tert- in hexanes): R_(f) = 0.2.butyl-dimethyl-silanyloxy)-pent-2-yn-1- ol 771-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 571.6 (M⁺+1); TLC (50%ether pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-4-(tert- in hexanes): R_(f) =0.3. butyl-dimethyl-silanyloxy)-but-2- yn-1-ol

General Preparation D

Combine the appropriate alcohol (1.0 eq) in dichloromethane, add 4 Åmolecular sieves (powder) and stir the mixture. After 10 min, addN-methyl morpholine N-oxide (2.0 eq) into the above mixture and stir.After 10 min, add TPAP (0.1 eq) to the mixture and stir at RT. After 20min, filter the mixture through a pad of silica gel and concentrate thefiltrate in vacuo. Purify the residue by flash chromatography on silicagel to give the title compound.

By the method of General Preparation D, using the appropriate startingmaterials, the following compounds are prepared and isolated.

Prep. # Product Physical Data 781-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 526.1 (M+1); TLC (30%chloro-1H-[1,2,3]triazol-4-yl]-4-(tert- Et₂O in hexanes): R_(f) = 0.2.butyl-dimethyl-silanyloxy)-but-2-yn-1- one 791-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 568.1 (M+1); TLC (50%phenyl-1H-[1,2,3]triazol-4-yl]-4-(tert- Et₂O in hexanes): R_(f) = 0.3.butyl-dimethyl-silanyloxy)-but-2-yn-1- one 801-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 539.9 (M⁺+1); TLC (50%chloro-1H-[1,2,3]triazol-4-yl]-5-(tert- ether in hexanes): R_(f) = 0.2.butyl-dimethyl-silanyloxy)-pent-2-yn-1- one 811-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 582.9 (M⁺+1); TLC (50%pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-5-(tert- EtOAc in hexanes): R_(f) =0.4. butyl-dimethyl-silanyloxy)-pent-2- yn-1-one 821-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 569.0 (M⁺+1); TLC (50%pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-4-(tert- EtOAc in hexanes): R_(f) =0.1. butyl-dimethyl-silanyloxy)-but-2-yn- 1-one

Preparation 831-[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-]H-[1,2,3)triazol-4-yl]-3-(2-chloro-phenyl)-propynone

Dissolve1-[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazol-4-yl]-3-(2-chloro-phenyl)-prop-2-yn-1-ol(33.5 g, 67.8 mmol) in CH₂Cl₂ (300 mL) and treat with MnO₂ (50.0 g, 556mmol). Stir mixture at RT overnight then filter through a pad of Celite®and concentrate the filtrate. Purify the crude material by trituratingwith 30% ether/hexanes. MS (ES) 492.1 (M+1). ¹H NMR (400 MHz, CDCl₃) δ7.89 (s, 1H), 7.81 (s, 2H), 7.47 (dd, 1H, J=1.5, 7.8 Hz), 7.46 (dd, 1H,J=1.4, 7.8 Hz), 7.40 (dt, 1H, J=1.5, 7.4 Hz), 7.29 (dt, 1H, J=1.5, 7.4Hz), 5.68 (s, 2H).

General Preparation E

Under N₂, charge an oven-dried flask with oxalyl chloride (2 M inCH₂Cl₂, 1.2 eq) and chill in a dry ice/acetone slush. Add DMSO (3 eq)slowly by syringe and stir 45 min. Add the alcohol of interest (1 eq) inanhydrous CH₂Cl₂ (0.4 M) slowly by syringe and stir 1 h. Then add TEA (5eq) slowly by syringe and stir for 90 min. while the bath is allowed towarm to RT. Quench the reaction with saturated aqueous NH₄C₁ and H₂O,extract with ether, wash combined organics with brine, dry over MgSO₄,filter, and concentrate under vacuum. Purify by chromatography on silicagel.

By the method of General Preparation E, using the appropriate startingmaterials, the following compounds may be prepared and isolated.

Prep. # Product Physical Data 841-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 500.1 (M+1), TLC R_(f)= 0.55 phenyl-1H-[1,2,3]triazol-4-yl]-3-phenyl- (50% EtOAc/Hexane)propynone 85 1-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 518.2(M+1), TLC R_(f) = 0.55 phenyl-1H-[1,2,3]triazol-4-yl]-3-(4- (50%EtOAc/Hexane) fluoro-phenyl)-propynone 861-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 568.0 (M+1), TLC R_(f)= 0.57 phenyl-1H-[1,2,3]triazol-4-yl]-3-(3- (50% EtOAc/Hexane)trifluoromethyl-phenyl)-propynone 871-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 518.0 (M+1), TLC R_(f)= 0.48 phenyl-1H-[1,2,3]triazol-4-yl]-3-(2- (50% EtOAc/Hexane)fluoro-phenyl)-propynone

Preparation 881-[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]4-trimethylsilanyloxy-pent-2-yn-1-one

Dissolve 3-methyl-3-trimethylsilyloxy-1-butyne (1.17 g, 7.5 mmol, 3 eq)in THF (7 mL) and cool to 0° C. Add ethylmagnesium bromide (2.3 mL of a3.0 M solution in ether, 7.5 mmol, 3 eq) dropwise and stir at 0° C. for30 min. Add1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazole-4-carbaldehyde(1.0 g, 2.5 mmol) as a solution in THF (7 mL). Stir at 0° C. for 1 h,then warm to RT. After 3 h, quench by adding saturated NH₄Cl (25 mL).Extract with EtOAc (2×25 mL), wash the combined organic layers withbrine (25 mL), dry (MgSO₄), filter, and concentrate.

Redissolve the crude alcohol in CH₂Cl₂ (12.5 mL) and add activatedmanganese oxide (1.09 g, 12.5 mmol, 5 eq.). Sonicate the mixture for 2min, then stir at RT for 24 h. Filter the mixture through a plug ofCelite® and concentrate the filtrate. Purify the residue bychromatography (silica gel, hexanes/EtOAc 3:1 to 1:1 gradient) toprovide 605 mg (44%) of the desired alkynyl ketone. TLC: R_(f)=0.51 (1:2hexanes/EtOAc); MS(ES): 555.1 (M+1), 465.1 (M−OSiMe₃).

Using a method similar to Preparation 88, with the appropriate startingmaterials, the following compounds may be prepared and isolated.

Prep. # Product Physical Data 891-[1-(3,5-bis-trifluoromethyl-benzyl)-5- TLC: R_(f) = 0.33 (1:2 hexanes/pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-4- EtOAc) MS (ES) 469.1 (M+1)methoxy-but-2-yn-1-one 90 1-[1-(3,5-bis-trifluoromethyl-benzyl)-5- m.p.= 105° C. pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-4- TLC: R_(f) = 0.86 (1:2hexanes/ methyl-4-trimethylsilanyloxy-pent-2-yn- EtOAc) MS (ES) 555.2(M+1), 1-one 465.2 [(M-OSiMe₃)⁺] 911-[1-(3,5-bis-trifluoromethyl-benzyl)-5- m.p. 87–90° C.chloro-1H-[1,2,3]triazol-4-yl]-4-tert- TLC: R_(f) = 0.55 (2:1 hexanes/butoxy-pent-2-yn-1-one EtOAc) MS (ES) 482.0 (M+1), 426.0 [(M-C (CH₃)₃)⁺]92 1-[1-(3,5-bis-trifluoromethyl-benzyl)-5- m.p. 94–96° C.chloro-1H-[1,2,3]triazol-4-yl]-4- TLC: R_(f) = 0.35 (2:1 hexanes/methoxy-but-2-yn-1-one EtOAc) MS (ES) 426.0 (M+1) 931-[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro- TLC: R_(f) = 0.58 (2:1hexanes/ 1H-[1,2,3]triazol-4-yl]-4-methyl- EtOAc) MS (ES) 511.9 (M+1),4-trimethylsilanyloxy-pent-2-yn-1-one 422.0 [(M-OSiMe₃)⁺]

Preparation 941-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-3-(2-chloro-phenyl)-propynone

Chill a solution of 1-chloro-2-ethynylbenzene (4.0 mL, 32.8 mmol) inanhydrous THF (25 mL) under nitrogen to 0° C. Add by syringeethylmagnesium bromide, 3.0 M in ether (9.7 mL, 29.3 mmol), whilestirring. After 30 min, remove from ice-bath and add by syringe asolution of1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carboxylicacid methoxy-N-methyl-amide (10.73 g, 23.4 mmol) in THF (35 mL). After 2h, quench with saturated aqueous NH₄Cl and extract with EtOAc, dry overMgSO₄, filter and concentrate under vacuum. Purify by chromatography(silica gel, hexanes/EtOAc gradient) to give the title compound: MS (ES)534.0 (M+1), ¹H NMR (300 MHz, CDCl₃): δ 7.82 (s, 1H), 7.56–7.12 (m,11H), 5.59 (s, 2H).

By a method similar to Preparation 94, using the appropriate startingmaterials, the following compounds may be prepared.

Prep. # Product Physical Data 951-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 472.1 (M+H), 470.1(M−H); ¹H methyl-1H-[1,2,3]triazol-4-yl]-3-(2- NMR (400 MHz, CDCl₃) δ7.90 (s, 1H), chloro-phenyl)-propynone 7.75 (dd, 1H, J = 7.9, 1.6 Hz),7.71 (s, 2H), 7.47 (dd, 1H, J = 8.2, 1.3 Hz), 7.41 (dt, 1H, J = 7.9, 1.6Hz), 7.31 (dt, 1H, J = 8.2, 1.3 Hz), 5.66 (s, 2H), 2.61 (s, 3H) 961-[1-(3,5-bis-trifluoromethyl-benzyl)-5- m.p. 50–54° C.;pyridin-4-yl-1H-[1,2,3]triazole-4-yl]-3-(2- MS (m/e): 535 (M+H⁺);chloro-phenyl)-propynone TLC: R_(f) = 0.34 (2:1 EtOAc:Hexanes) 971-[1-(3,5-bis-trifluoromethyl-benzyl)-5- m.p. 100–101° C.; MS (m/e): 535(M+H⁺); pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-3-(2- TLC: R_(f) = 0.12(1:1 chloro-phenyl)-propynone EtOAc:Hexanes). 981-[1-(3,5-bis-trifluoromethyl-benzyl)-5- m.p. 168–169° C.; MS (m/e): 536(M+H+); pyrimidin-5-yl-1H-[1,2,3]triazol-4-yl]-3-(2- TLC: R_(f) = 0.27(Silica, 1:1 EtOAc:Hexanes). chloro-phenyl)-propynone 991-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 570.2 (M+). TLC R_(f) =0.40 (40% pyrazin-2-yl-1H-[1,2,3]triazol-4-yl]-4-(tert- EtOAc/hexanes)butyl-dimethyl-silanyloxy)-but-2- yn-1-one 1001-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 556.1 (M+). TLC R_(f) =0.31 (30% pyrazin-2-yl-1H-[1,2,3]triazol-4-yl]-4- EtOAc/hexanes)methyl-4-trimethylsilanyloxy-pent-2-yn- 1-one 1011-[1-(3,5-Bis-trifluoromethyl-benzyl)-5- MS (ES) 536.0 (M+)pyrazin-2-yl-1H-[1,2,3]triazol-4-yl]-3-(2- TLC R_(f) = 0.62 (1:1EtOAc/hexanes) chlorophenyl)-propynone 1023-(2-chloro-phenyl)-1-[1-(3,5-dichloro- MS (ES)467.1, 469.1 (M+1)⁺.R_(f) = 0.52 benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol- (6.7%MeOH/CH₂Cl₂). 4-yl]-propynone 1033-(2-chloro-phenyl)-1-[1-(3,5-dichloro- MS (ES)466.9, 468.9 (M+1)⁺.R_(f) = 0.51 benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol- (6.7%MeOH/CH₂Cl₂). 4-yl]-propynone 1043-(2-chloro-phenyl)-1-[5-pyridin-3-yl-1-(3- MS (ES) 467.2, 469.2 (M+1)⁺.R_(f) = 0.41 trifluoromethyl-benzyl)-1H- (6.7% MeOH/CH₂Cl₂).[1,2,3]triazol-4-yl]-propynone 1053-(2-chloro-phenyl)-1-[5-pyridin-3-yl-1-(4- MS (ES) 467.2, 469.2 (M+1)⁺.R_(f) = 0.40 trifluoromethyl-benzyl)-1H- (6.7% MeOH/CH₂Cl₂)[1,2,3]triazol-4-yl]-propynone 1061[1-(2,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 535.1, 537.1 (M+1)⁺.R_(f) = 0.67 pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-3-(2- (6.7%MeOH/CH₂Cl₂) chloro-phenyl)-propynone 1073-(2-chloro-phenyl)-1-[1-(2-methoxy-5- MS (ES+) 513.1 (M+ 1)⁺. ¹H NMR(400 trifluoromethoxy-benzyl)-5-pyridin-3-yl- MHz, CDCl₃) δ 8.69 (dd,1H, J = 1.5, 1H-[1,2,3]triazol-4-yl]-propynone 4.9 Hz), 8.52 (d, 1H, J =1.5 Hz), 7.65 (dt, 1H, J = 2.0, 7.8 Hz), 7.61 (dd, 1H, J = 2.0, 7.8 Hz),7.42 (m, 1H), 7.36 (m, 2H), 7.25 (dt, 1H, J = 1.5, 7.8 Hz), 7.12 (dd,1H, J = 2.0, 8.8 Hz), 6.88 (d, 1H, J = 2.9 Hz), 6.75 (d, 1H, J = 9.3Hz), 5.47 (s, 2H), 3.62 (s, 3H). 1083-(2-Chloro-phenyl)-1-[1-(3,4-difluoro- MS (ES) 435.2, 437.2 (M⁺+1);benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol- R_(f) = 0.48 (50%EtOAc/CH₂Cl₂) 4-yl]-propynone

General Preparation F

Treat a solution of the appropriate N-methoxy-N-methyl-amide (1.0 eq.)in THF with ethynylmagnesium bromide (2.0 eq) at 0° C. Stir the mixturefor 2 h, then warm to RT. Add aqueous saturated NH₄Cl solution slowly.Extract with ether. Dry the combined organic layers with anhydrousMgSO₄, filter and concentrate in vacuo. Purify by chromatography onsilica gel.

By the method of General Preparation F, the following compounds may beprepared.

Prep. # Product Physical Data 1091-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 486.2pyridin-4-yl-1H-[1,2,3]triazol-4-yl]- (M⁺+1);TLC (33%3-(methoxy-methyl-amino)-2-propenone acetone in hexanes): R_(f) = 0.1.110 1-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 486.2pyridin-3-yl-1H-[1,2,3]triazol-4-yl]- (M⁺+1); TLC (33%3-(methoxy-methyl-amino)-2-propenone acetone in hexanes): R_(f) = 0.1.111 1-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 443.1chloro-1H-[1,2,3]triazol-4-yl]- (M⁺+1); TLC (33%3-(methoxy-methyl-amino)-2-propenone acetone in hexanes): R_(f) = 0.1.

Preparation 112 (1,1-dimethyl-2-nitro-ethoxy)-trimethyl-silane

To a solution of nitromethane (100 g, 1.64 mmol) and acetone (5 mL), adda catalytic amount of tetramethylguanidine. Using a syringe pump, addacetone (115 mL, 1.64 mmol) over a period of 72 h. to the stirredsolution at RT. In a separate flask, combine chlorotrimethylsilane (206mL, 1.64 mmol) and imidazole (123 g, 1.8 mmol) at 0° C. Transfer thenitromethane/acetone solution into the trimethylsilyl-imidazole mixtureand allow the resulting mixture to stir 18 h at RT. Then cool thereaction to 0° C., dilute with cold ether (450 mL) and wash with cold 1NHCl (200 mL×2). Wash the organic layer with brine (300 mL). Carefullyconcentrate the crude material in vacuo without heating. Purify bydistillation to provide the title compound. ¹H NMR (300 MHz, CDCl₃) δ4.20 (s, 2H), 1.28 (s, 6H), 0.01 (s, 9H).

Preparation 113 1-Iodo-2-methoxy-ethane

Add sodium iodide (70.5 g, 0.47 mol) to a solution of1-bromo-2-methoxy-ethane (47.0 g, 0.34 mol) in acetone and warm toreflux. After 50 h, pour the reaction mixture into ice water and extractwith ether. Wash the organic layer with saturated sodium thiosulfatesolution (3×), then water and brine. Dry over Na₂SO₄, filter, andconcentrate under reduced pressure to give the title compound (54.0 g,87%). ¹H NMR (400 MHz, CDCl₃) δ 3.65 (t, 2H, J=6.9 Hz), 3.40 (s, 3H),3.26 (t, 2H, J=6.9 Hz).

General Preparation G

Combine the alkyl halide of interest (1 eq) and AgNO₂ (1.1 eq) in ether,cover flask with aluminum foil and heat to reflux. Add additional AgNO₂(0.3 eq) if necessary until complete by TLC. Then cool to RT and filterthe mixture through Celite®. Dry the filtrate over MgSO₄, filter, andconcentrate. Purify by vacuum distillation or by flash chromatography onsilica gel.

By the method of General Preparation G, the following compounds may beprepared and isolated.

Prep. # Product Physical Data 114 2-(2-nitro- ¹H NMR (CDCl₃, 400 MHz): δ5.02 (t, J = 3.7 ethyl)- Hz, 1H), 4.50 (t, J = 6.7 Hz, 2H), 4.02–3.94[1,3]dioxolane (m, 4H), 2.43 (m, 2H). 115 1-methoxy-2- GC/MS [EI⁺] 105.0(M)⁺; ¹H NMR (400 MHz, nitro-ethane CDCl₃) δ 4.51 (t, 2H, J = 4.8 Hz),3.90 (t, 2H, J = 4.8 Hz), 3.37 (s, 3H). 116 nitromethyl- GC/MS [EI⁺]101.0 (M)⁺; ¹H NMR (400 MHz, cyclopropane CDCl₃) δ 4.20 (d, 2H, J = 7.3Hz), 1.48 (m, 1H), 0.76 (m, 2H), 0.45 (m, 2H).

Preparation 117[1-(3,5-bis-trifluoromethylbenzyl)-5-chloro-1H-[1,2,3]triazol-4-yl]-[5-(2chlorophenyl)-3-(tetrahydropyran-2-yloxymethyl)-isoxazol-4-yl]-methanone

Add triethylamine (17.9 mL, 0.128 mol) to a slurry of1-[1-(3,5-bistrifluoromethylbenzyl)-5-chloro-1H-[1,2,3]triazol-4-yl]-3-(2-chlorophenyl)-propynone(60.0 g, 0.122 mol) and 1,4-diphenylene diisocyanate (58.6 g, 0.366 mol)in toluene (450 mL). Heat reaction to 80° C. and add a solution of2-(2-nitroethoxy)tetrahydropyran (34.0 mL, 0.241 mol) in toluene (200mL) over 3 h, then heat for an additional 5.5 h. Add more triethylamine(2.7 mL, 0.019 mol), 1,4-diphenylene diisocyanate (8.8 g, 0.055 mol),and 2-(2-nitroethoxy)tetrahydropyran (5.1 mL, 0.036 mol) and heat anadditional 4 h. Stir overnight at RT, then filter through Celite® andconcentrate filtrate under vacuum to an oil. With vigorous stirring, addheptane (1 L) over 30 min, stir for an additional 30 min, filter and dryto obtain crude title compound. Add the crude product to diethyl ether(700 mL), treat with acid-washed carbon (4 g), and filter throughCelite®. Concentrate the solution to give 108 g of material. Add heptane(500 mL) over 30 min, stir 1 h, filter, and dry to obtain the titlecompound: MS (m/e): 649 (M⁺). Analysis for C₁₄H₁₁ClF₆N₄O₂: calculated:C, 40.35; H, 2.66; N, 13.44. Found: C, 40.03; H, 2.70; N, 13.33.

By a method similar to Preparation 117, using the appropriate conditionsand starting materials, the following compounds may be prepared andisolated.

Prep. # Product Physical Data 118 [1-(3,5-bis-trifluoromethyl-benzyl)-5-MS (aspci): m/z = 633.9 (M-(OMe)⁺); ¹Hphenyl-1H-[1,2,3]triazol-4-yl]-[5-(2- NMR (250 MHz, CDCl₃) δ 7.72 (s,1H), chloro-phenyl)-3-(2,2-dimethoxy- 7.59 (dd, J = 6.2, 2.7 Hz, 1H),7.48–7.10 (m, ethyl)-isoxazol-4-yl]-methanone 10 H), 5.37 (s, 2H), 4.70(t, J = 6.2 Hz, 1H), 3.41 (s, 6H), 3.70 (q, J = 6.25 Hz, 2H), 3.21 (s,6H), 3.1–3.2 (m, 2H). 119 [1-(3,5-bis-trifluoromethyl-benzyl)-5- ¹H NMR(300 MHz, CDCl₃) δ 1.34–1.70 (m, pyridin-3-yl-1H[1,2,3]triazol-4-yl]-{5-(2- 6H), 3.23 (dt, 2H, J = 6.84, 1.70 Hz),chloro-phenyl)-3-[2-(tetrahydro- 3.41–3.51 (m, 1H), 3.72–3.79 (m, 2H),pyran-2-yloxy)-ethyl]-isoxazol-4-yl}- 4.07 (dt, J = 9.83, 6.68 Hz, 1H),4.59 (t, methanone J = 3.30 Hz, 1H), 5.47 (s, 2H), 7.21 (dd, J = 7.06,1.17 Hz, 1H), 7.32–7.36 (m, 3H), 7.39–7.44 (m, 2H), 7.61 (dt, J = 7.82,2.12, 1H), 7.71 (dd, 1H, J = 7.64, 1.76 Hz), 7.83 (s, 1H), 8.50 (d, 1H,J = 2.05 Hz), 8.78 (dd, 1H, J = 4.87, 1.47 Hz). 120[1-(3,5-bis-trifluoromethyl-benzyl)-5- Exact Mass 691.14; MS (ESI) 714.1m/z pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-[5-(2- (M+Na); ¹H NMR (300 MHz,CDCl₃) chloro-phenyl)- δ1.38–1.80 (m, 6H), 3.48 (m, 1H) 3.78 (m,3-(tetrahydro-pyran-2-yloxymethyl)- 1H), 4.69 (m, 1H), 4.93 (ABq, 2H, J= 13.31 Hz, isoxazol-4-yl]-methanone Δν = 64.63 Hz) 5.47 (s, 2H), 7.16(m, 2H), 7.24 (m, 1H), 7.33–7.43 (m, 4H), 7.70 (dd, 1H, J = 7.51, 2.04Hz), 7.86 (s, 1H), 8.78 (m, 2H). 121[1-(3,5-bis-trifluoromethyl-benzyl)-5- ¹H NMR (300 MHz, CDCl₃) δ1.40–1.72 (m, pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-[5-(2- 6H), 3.45–3.50(m, 1H), 3.75–3.81 (m, chloro-phenyl)-3-(tetrahydro-pyran- 1H), 4.69 (t,1H, J = 3.23 Hz), 4.94 (ABq, 2-yloxymethyl)-isoxazol-4-yl]- 2H, J =13.19, Δν = 66.43 Hz), 5.51 (s, methanone 2H), 7.25–7.30 (m, 1H),7.35–7.44 (m, 5H), 7.57–7.60 (m, 1H), 7.69–7.71 (m, 1H), 7.84 (s, 1H),8.48 (d, 1H, J = 2.1 Hz), 8.76 (dd, 1H, J = 4.86, 1.67 Hz); TLC R_(f) =0.3 (10% ether/dichloromethane). 122[1-(3,5-bis-trifluoromethyl-benzyl)-5- ¹H NMR (300 MHz, CDCl₃) δ1.32–1.72 (m, pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-{5-(2- 6H), 3.23 (td,2H, J = 6.75, 1.39 Hz) chloro-phenyl)-3-[2-(tetrahydro- 3.44 (m, 1H),3.76 (m, 2H), 4.07 (dt, 1H, pyran-2-yloxy)-ethyl]-isoxazol-4-yl}- J =9.76, 6.83 Hz), 4.60 (bt, 1H, J = 3.32 Hz) methanone 5.43 (s, 2H),7.17–7.20 (m, 3H), 7.32–7.43 (m, 4H), 7.72 (dd, 1H, J = 7.71, 1.66 Hz),7.86 (s, 1H), 8.80 (m, 2H). 123 [1-(3,5-bis-trifluoromethyl-benzyl)-5-MS (ES) 691.2 (M+1), ¹H NMR (300 MHz,phenyl-1H-[1,2,3]triazol-4-yl]-[5-(2- CDCl₃): δ 7.84 (s, 1H), 7.72–7.18(m, chloro-phenyl)-3-(tetrahydro-pyran-2- 11H), 5.48 (s, 2 H), 4.96 (m,2H), yloxymethyl)-isoxazol-4-yl]-methanone 4.73 (m, 1H), 3.81 (m, 1H),3.50 (m, 1H), 1.80–1.37 (m, 6H). 124[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 663.1 (M+1), ¹H NMR (300MHz, phenyl-1H-[1,2,3]triazol-4-yl]-[5-(2- CDCl₃): δ 7.80 (s, 1H), 7.67(dd, J = 7.8 Hz, chloro-phenyl)-3-[1,3]dioxolan-2- 1.7 Hz, 1H),7.56–7.16 (m, ylmethyl-isoxazol-4-yl]-methanone 10H), 5.44 (s, 2H), 5.29(t, J = 4.2 Hz, 1H), 3.84–3.74 (m, 4H), 3.33 (d, J = 4.4 Hz, 2H). 125[1-(3,5-bis-trifluoromethyl-benzyl)-5- ¹H NMR (300 MHz, CDCl₃): δ 9.18(d, J = 1.3 pyrazin-2-yl-1H-[1,2,3]triazol-4-yl]-[5-(2- Hz, 1H), 8.68(m, 2H), 7.80 (s, 1H), chlorophenyl)-3-[1,3]dioxolan-2-yl- 7.68 (m, 1H),7.59 (s, 2H), 7.38–7.24 (m, methyl-isoxazol-4-yl]-methanone 2H), 7.19(m, 1H), 5.84 (s, 2H), 5.27 (t, J = 4.1 Hz, 1H), 3.78 (m, 4H), 3.38 (d,J = 4.1 Hz, 2H); TLC R_(f) = 0.13 (50% EtOAc/Hexane). 126[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 705.5 (M+1); TLC R_(f) =0.15 (30% phenyl-1H-[1,2,3]triazol-4-yl]-{5-(2- EtOAc/Hexane).chloro-phenyl)-3-[2-(tetrahydro-pyran- 2-yloxy)-ethyl]-isoxazol-4-yl}-methanone 127 [1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 693.2 (M+1)pyrazin-2-yl-1H-[1,2,3]triazol-4-yl]- TLC R_(f) = 0.50 (10%CH₃CN/CH₂Cl₂) [5-(2-chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-4-yl]- methanone 128[5-(2-chloro-phenyl)-3-(tetrahydro- MS (ES) 624.2, 626.2 (M+1)⁺pyran-2-yloxymethyl)-isoxazol-4-yl]-[1-(3,5-dichloro-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-methanone 129[5-(2-chloro-phenyl)-3-(tetrahydro- MS (ES) 624.1, 626.1 (M+1)⁺pyran-2-yloxymethyl)-isoxazol-4-yl]-[1-(3,5-dichloro-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-methanone 130[5-(2-chloro-phenyl)-3-(tetrahydro- MS (ES) 624.2, (M+1)⁺; R_(f) = 0.22(6.7% pyran-2-yloxymethyl)-isoxazol-4-yl]- MeOH/CH₂Cl₂).[5-pyridin-3-yl-1-(3-trifluoromethyl- benzyl)-1H-[1,2,3]triazol-4-yl]-methanone 131 [5-(2-chloro-phenyl)-3-(tetrahydro- MS (ES) 624.2, (M+1)⁺;R_(f) = 0.20 (6.7% pyran-2-yloxymethyl)-isoxazol-4-yl]- MeOH/CH₂Cl₂)[5-pyridin-3-yl-1-(4-trifluoromethyl- benzyl)-1H-[1,2,3]triazol-4-yl]-methanone 132 [1-(2,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 692.2,694.2, (M+1)⁺. R_(f) = 0.43 (6.7% pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-MeOH/CH₂Cl₂) [5-(2-chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-4-yl]- methanone 133[1-(3,5-bis-trifluoromethyl-benzyl)-5- R_(f) = 0.49 (2:1 Hex/EtOAc);pyrazin-2-yl-1H-[1,2,3]triazol-4-yl]- MS (ES) 709.2 (M+1)[5-(2-chloro-phenyl)-3-(1-methyl-1-trimethylsilanyloxy-ethyl)-isoxazol-4- yl]-methanone 134[1-(3,5-bis-trifluoromethyl-benzyl)-5- R_(f) = 0.85 (1:1 Hex/EtOAc);chloro-1H-[1,2,3]triazol-4-yl]-[5-(2- MS (ES) 665.1 (M+1)chloro-phenyl)-3-(1-methyl-1- trimethylsilanyloxy-ethyl)-isoxazol-4-yl]-methanone 135 [1-(3,5-bis-trifluoromethyl-benzyl)-5- R_(f) = 0.31(3:1 Hex/EtOAc); phenyl-1H-[1,2,3]triazol-4-yl]-[5-(2- MS/ES (M+1):707.2 chloro-phenyl)-3-(1-methyl-1-trimethylsilanyloxy-ethyl)-isoxazol-4- yl]-methanone 136[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 579.2 (M+H).chloro-1H-[1,2,3]triazol-4-yl]-[5-(2- ¹H NMR (400 MHz, CHCl₃) δ 7.91 (s,chloro-phenyl)-3-methoxymethyl- 1H), 7.66–7.68 (m, 3H), 7.31–7.39 (m,isoxazol-4-yl]-methanone 2H), 7.22 (dd, 1H, J = 7.7, 1.5 Hz), 5.59 (s,2H), 4.80 (s, 2H), 3.36 (s, 3H). 137[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 575.0 (M+H).chloro-1H-[1,2,3]triazol-4-yl]-[5-(2- ¹H NMR (400 MHz, CDCl₃) δ 7.92 (s,chloro-phenyl)-3-cyclopropyl-isoxazol- 1H), 7.67 (s, 2H), 7.62 (dd, 1H,J = 7.8, 4-yl]-methanone 1.4 Hz), 7.32 (dt, 1H, J = 7.8, 1.0 Hz), 7.26(dt, 1H, J = 7.8, 1.4 Hz), 7.13 (dd, 1H, J = 7.8, 1.0 Hz), 5.55 (s, 2H),2.31 (m, 1H), 1.16 (m, 2H), 1.06 (m, 2H). 138[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES+) 549.0 (M+1). ¹H NMR (400MHz, chloro-1H-[1,2,3]triazol-4-yl]-[5-(2- CDCl₃) δ 7.89 (s, 1H), 7.65(s, 2H), chloro-phenyl)-3-methyl-isoxazol-4-yl]- 7.62 (dd, 1H, J = 1.5,7.8 Hz), 7.32 (dt, methanone 1H, J = 1.4, 7.4 Hz), 7.26 (dt, 1H, J =1.4, 7.8 Hz), 7.11 (dd, 1H, J = 1.0, 7.8 Hz), 5.53 (s, 2H), 2.52 (s,3H). 139 [1-(3,5-Bis-trifluoromethyl-benzyl)-5- Exact Mass 689.1; MS(aspci): 690.0 phenyl-1H-imidazol-4-yl]-[5-(2-chloro- (M+1), 687.9(M−1); ¹ H NMR (300 MHz, phenyl)-3-(tetrahydro-pyran-2- CDCl₃) δ 7.72(s, 1H), 7.45 (m, 1H), 7.32 (s, yloxymethyl)-isoxazol-4-yl]-methanone1H), 7.32–7.18 (m, 6H), 7.10 (s, 2H), 7.02–7.08 (m, 2H), 5.02 (s, 2H),4.81 (abq, J = 13.5, 22.5 Hz, 2H), 4.58 (m, 1H), 3.69 (m, 1H), 3.37 (m,1H), 1.30–1.70 (m, 6H). 140 [5-(2-Chloro-phenyl)-3-(tetrahydro- MS (ES)592.2 (M⁺+1), Rf = 0.42 (50% pyran-2-yloxymethyl)-isoxazol-4-yl]-EtOAc/CH₂Cl₂) [1-(3,4-difluoro-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-methanone

Preparation 141[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-3-[1,3]dioxolan-2-ylmethyl-3H-[1,2,3]triazol-4-yl]-methanone

In a pressure vessel, combine1-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-3-(2-chloro-phenyl)-propynone(0.506 g, 1 eq) in toluene (0.1 M), and 2-azido-methyl-[1,3]dioxolane(0.241 g, 2 eq). Heat in a 120° C. bath for 48 h. Then concentrate andpurify by chromatography on silica gel to give the title compound. MS(ES) 663.6 (M+1), ¹H NMR (300 MHz, CDCl₃): & 7.85 (br s, 1H), 7.78 (dd,J=7.7, 1.6 Hz, 1H), 7.61–7.49 (m, 3H), 7.41–7.10 (m, 7H), 5.46 (s, 2H),5.32 (t, J=3.0 Hz, 1H), 4.97 (d, J=3.0 Hz, 2H), 3.70 (m, 4H).

Using a method similar to Preparation 141, the following compound may beprepared.

Prep. # Product Physical Data 142 [1-(3,5-bis-trifluoromethyl-benzyl)-5-MS (ES) 735.2 (M+1); phenyl-1H-[1,2,3]triazol-4-yl]-[3- TLC R_(f) 0.35(2% [2-(tert-butyl-dimethyl-silanyloxy)- MeOH/CH₂Cl₂)ethyl]-5-(2-chloro-phenyl)-3H- [1,2,3]triazol-4-yl]-methanone

Preparation 143[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-1H-[1,2,3]triazol-4-yl]-methanone

Add trimethylsilylazide (4.0 mL, 30.1 mmol) to a solution of1-[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazol-4-yl]-3-(2-chloro-phenyl)-propynone(1.50 g, 3.04 mmol) in toluene (12 mL) in a sealed tube. Heat thesolution to 110° C. for 8 h, then cool to RT and add additionaltrimethylsilyl azide (2.0 mL, 15 mmol). Heat to 110° C. for 16 h. Coolsolution to RT, concentrate in vacuo, then add ether. Isolate the whitepreciptate by filtration to give 475 mg of the title compound.Concentrate the filtrate and purify the residue by flash chromatographyusing a linear gradient of 20% to 80% EtOAc/hexanes to give another 550mg of the desired product. The solids are combined and dried undervacuum. (1.0 g, 63%). MS (ES+) 535.0 (M+1), MS (ES−) 533.0 (M−1); ¹H NMR(400 MHz, CDCl₃) δ 14.56 (br s, 1H), 7.89 (s, 1H), 7.81 (s, 2H), 7.48(m, 2H), 7.36 (m, 2H), 5.74 (s, 2H).

Preparation 144[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazol-4-yl]-[4-(2-chloro-phenyl)-2H-pyrazol-3-yl]-methanoneand[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-1H-pyrazol-4-yl]-methanone

Add trimethylsilyldiazomethane (0.40 mL, 2 M in hexane) to a solution of1-[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazol-4-yl]-3-(2-chloro-phenyl)-propynone(0.15 g, 0.32 mmol) in 1:1 mixture THF and ether (2.0 mL). Stir at RTfor 1 to 3 days, then concentrate under vacuum and purify the residue byflash chromatography (silica gel, hexanes/EtOAc gradient). Isomer 1: MS[ES] 534.1 (M+H)⁺; ¹H NMR (400 MHz, CHCl₃) δ 7.92 (s, 1H), 7.83 (s, 2H),7.73 (s, 1H), 7.47 (m, 1H), 7.37 (m, 1H), 7.26–7.33 (m, 2H), 5.72 (s,2H). Isomer 2: MS [ES] 534.1 (M+H)⁺; ¹H NMR (400 MHz, CHCl₃) δ 9.01 (s,1H), 7.92 (s, 1H), 7.81 (s, 2H), 7.43–7.48 (m, 2H), 7.32–7.40 (m, 2H),5.68 (s, 2H).

General Preparation H

Slowly add the appropriate halo-pyridine substrate (1 eq) to a cooled(−60 to −70° C.) solution of LDA (1.2 eq) in THF and stir for 1–3 h.Then add DMF (1.7 eq) dropwise the cold mixture for 1–2 h. Allow themixture to warm to RT, quench with water, act with EtOAc. Dry thecombined extracts over Na₂SO₄ and concentrate. Purify by chromatographyon silica gel.

Using the method of General Preparation H, the following compounds maybe prepared and isolated.

Prep. # Product Physical Data 145 3-chloropyridine-4- MS (ES) 142.1(M+1) carboxaldehyde 146 4-chloropyridine-3- MS (ES) 142.0, 144.0 (M+1)carboxaldehyde 147 2-chloropyridine-3- MS (electron impact) 141.2, 143.3(M+) carboxaldehyde

General Preparation I

Combine the appropriate aldehyde (1 eq) with hydroxylamine hydrochloride(1.1 eq) in a mixture of EtOH, water, and ice. Slowly add 1N NaOH (2.5eq) and stir the mixture 2–4 h at RT. Adjust to pH 7 and extract withEt₂O or EtOAc. Dry the combined extracts over Na₂SO₄, concentrate, anddry the resulting solid. Use without further purification.

Using the above method, the following compounds may be prepared.

Prep. # Product Physical Data 148 3-chloropyridine-4-carboxaldehyde MS(ES) 157.1, 159.1 (M+1)⁺. R_(f) = 0.21 oxime (6.25% MeOH/CH₂Cl₂). 1494-chloropyridine-3-carboxaldehyde MS (ES) 157.1, 159.1 (M+1) oxime 1502-chloropyridine-3-carboxaldehyde MS (EI) 156.3, 158.3 (M+) oxime 1512,6-dichlorobenzaldehyde oxime R_(f) = 0.51 (20:1 CHCl₃/MeOH); m.p. =146.7–148.0° C. 152 2,6-difluorobenzaldehyde oxime R_(f) = 0.35 (50:1CHCl₃/MeOH); m.p. = 109.7–111.1° C.

General Preparation J

Combine the appropriate oxime (1 eq) with N-chlorosuccinimide (1–1.2 eq)in DMF and stir at RT until reaction is complete. Then pour the reactionmixture into ice water and extract with Et₂O or EtOAc. Wash the combinedextracts with water and dry over Na₂SO₄. Concentrate and dry theresulting solid under reduced pressure. Use without furtherpurification.

Using the method of General Preparation J, the following compounds maybe prepared and isolated.

Prep. # Product Physical Data 153 3-chloropyridine-4-carboxaldehydeR_(f) = 0.71 (6.25% MeOH/CH₂Cl₂). ¹H chloro-oxime NMR (400 MHz, CDCl₃) δ7.67 (d, 1H, J = 5.1 Hz), 8.67 (d, 1H, J = 5.1 Hz), 8.81 (s, 1H), 12.97(s, 1H). 154 4-chloropyridine-3-carboxaldehyde ¹H NMR (400 MHz, CDCl₃) δ7.74 (d, chloro-oxime 1H, J = 5.5 Hz), 8.66 (d, 1H, J = 5.5 Hz), 8.74(s, 1H), 12.85 (s, 1H). 155 2-chloropyridine-3-carboxaldehyde MS (FD)190.0, 192.0 (M+) chloro-oxime 156 2,6-dichlorobenzaldehyde chloro-oximeR_(f) = 0.36 (6:1 Hex/EtOAc); m.p. = 78.5–79.8° C. 1572,6-difluorobenzaldehyde chloro-oxime m.p. = 109.8–110.8° C.

General Preparation K

Combine the appropriate chloro-oxime (1.0 eq) and the alkyne of interest(1.0 eq) in EtOAc or Et₂O (0.5 M). Add triethylamine (2.5 eq) and stirthe mixture at RT for 4–18 h. (The mixture may be heated to 50° C. tofacilitate the reaction if desired.) When the reaction is complete,treat the mixture with saturated sodium bicarbonate solution, andextract with ether (2 times). Dry the combined organic layers overMgSO₄, then filter and concentrate in vacuo. Purify the residue by flashchromatography on silica gel to give the title compound.

By the above method, the following compounds may be prepared andisolated.

Prep. # Product Physical Data 158 [1-(3,5-bis-trifluoromethyl-benzyl)-5-MS (ES) 679.1 (M+1); TLC R_(f) = 0.3 (50%chloro-1H-[1,2,3]triazol-4-yl]-[5-(tert- Et₂O in hexanes).butyl-dimethyl-silanyloxymethyl)-3-(2-chloro-phenyl)-isoxazol-4-yl]-methanone 159[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 721.2 (M+1); TLC R_(f) =0.2 (50% phenyl-1H-[1,2,3]triazol-4-yl]-[5-(tert- Et₂O in hexanes).butyl-dimethyl-silanyloxymethyl)-3-(2-chloro-phenyl)-isoxazol-4-yl]-methanone 160[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 692.9 (M⁺+1); TLC R_(f) =0.5 (50% chloro-1H-[1,2,3]triazol-4-yl]-[5- Et2O in hexanes).[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-(2-chloro-phenyl)-isoxazol-4-yl]- methanone 161[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 736.0 (M⁺+1); TLC R_(f) =0.3 (50% pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-[5- EtOAc in hexanes).[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-(2-chloro-phenyl)-isoxazol-4- yl]-methanone 162[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 723 (M⁺+1); TLC R_(f) =0.3 (50% pyridin-4-yl-1H-[1,2,3]triazol-4-yl]- EtOAc in hexanes).[5-(tert-butyl-dimethyl-silanyloxymethyl)-3-(2-chloro-phenyl)-isoxazol-4-yl]- methanone 163[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 722.0 (M⁺+1); TLC R_(f) =0.4 (50% pyridin-3-yl-1H-[1,2,3]triazol-4-yl]- EtOAc in hexanes).[5-(tert-butyl-dimethyl-silanyloxymethyl)-3-(2-chloro-phenyl)-isoxazol-4-yl]- methanone 164[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 723.3 (M+);pyrazin-2-yl-1H-[1,2,3]triazol-4-yl]- TLC R_(f) = 0.43 (40%EtOAc/hexanes) [5-(tert-butyl-dimethyl-silanyloxymethyl)-3-(2-chloro-phenyl)-isoxazol-4-yl]- methanone 165[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 709.2 (M+);pyrazin-2-yl-1H-[1,2,3]triazol-4-yl]- TLC R_(f) = 0.25 (30%EtOAc/hexanes) [3-(2-chloro-phenyl)-5-(1-methyl-1-trimethylsilanyloxy-ethyl)-isoxazol-4- yl]-methanone 166[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 709.1, 711.1 (M+1)⁺.pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-[3-(3-chloro-pyridin-4-yl)-5-(1-methyl-1-trimethylsilanyloxy-ethyl)-isoxazol-4- yl]-methanone 167[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 680.1, 683.1 (M+1)⁺;R_(f) = 0.21 chloro-1H-[1,2,3]triazol-4-yl]-[5-(tert- (6.25%MeOH/CH₂Cl₂). butyl-dimethyl-silanyloxymethyl)-3-(3-chloro-pyridin-4-yl)-isoxazol-4-yl]- methanone 168[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 680.1, 682.1 (M+1)chloro-1H-[1,2,3]triazol-4-yl]-[5-(tert-butyl-dimethyl-silanyloxymethyl)-3-(4-chloro-pyridin-3-yl)-isoxazol-4-yl]- methanone 169[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 680.3, 682.3 (M+1)⁺;R_(f) = 0.90 chloro-1H-[1,2,3]triazol-4-yl]-[5-(tert- (6.25%MeOH/CH₂Cl₂). butyl-dimethyl-silanyloxymethyl)-3-(2-chloro-pyridin-3-yl)-isoxazol-4-yl]- methanone 170[1-(3,5-bis-trifluoromethyl-benzyl)-5- R_(f) = 0.41 (3:1 Hex/EtOAc);chloro-1H-[1,2,3]triazol-4-yl]-[5-(tert- MS/ES (M+1) = 680.9butyl-dimethyl-silanyloxymethyl)-3-(2,6-difluoro-phenyl)-isoxazol-4-yl]- methanone 171[1-(3,5-bis-trifluoromethyl-benzyl)-5- R_(f) = 0.44 (3:1 Hex/EtOAc);chloro-1H-[1,2,3]triazol-4-yl]-[5-(tert- MS/ES (M+1) = 712.9butyl-dimethyl-silanyloxymethyl)-3-(2,6-dichloro-phenyl)-isoxazol-4-yl]- methanone 172[1-(3,5-bis-trifluoromethyl-benzyl)-5- TLC: R_(f) = 0.57 (2:1hexanes/EtOAc); chloro-1H-[1,2,3]triazol-4-yl]-[5-(1-tert- MS (ES) 634.9(M+1), 578.8 [(M− butoxy-ethyl)-3-(2-chloro-phenyl)- C (CH₃)₃)⁺]isoxazol-4-yl]-methanone 173 [1-(3,5-bis-trifluoromethyl-benzyl)-5- TLC:R_(f) = 0.63 (2:1 hexanes/EtOAc); chloro-1H-[1,2,3]triazol-4-yl]-[3-(2-MS (ES) 664.9 (M+1), 574.9 [(M− chloro-phenyl)-5-(1-methyl-1- OSiMe₃)⁺]trimethylsilanyloxy-ethyl)-isoxazol-4- yl]-methanone

General Preparation L

Dissolve the appropriate chlorotriazole (1 eq.) in the appropriate amine(20–120 eq.) and stir at 50–110° C. for 2–20 h. Dilute the solution withEtOAc and wash with 1N HCl, water, and saturated NaHCO₃. Dry the organiclayer over MgSO₄, then filter and concentrate. Purify the crude materialby flash chromatography on silica gel.

By the method of General Preparation L, using the appropriate startingmaterials, the following compounds may be prepared and isolated.

Prep. # Product Physical Data 174[1-(3,5-bis-trifluoromethyl-benzyl)-5-(4- MS (ES) 757.0 (M⁺+1); TLC (1%methyl-piperazin-1-yl)-1H-[1,2,3]triazol- MeOH in dichloromethane):R_(f) = 0.1. 4-yl]-[5-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-(2-chloro-phenyl)- isoxazol-4-yl]-methanone 175[1-(3,5-bis-trifluoromethyl-benzyl)- MS (ES) 760.0 (M⁺+1); TLC (33%5-(thiomorpholin-4-yl)-1H-[1,2,3]triazol-4- EtOAc in hexane): R_(f) =0.1. yl]-[5-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-(2-chloro-phenyl)- isoxazol-4-yl]-methanone 176[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 702.1 (M⁺+1); TLC (33%dimethylamino-1H-[1,2,3]triazol-4-yl]- EtOAc in hexane): R_(f) = 0.1.[5-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-(2-chloro-phenyl)-isoxazol-4- yl]-methanone 177[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 744.0 (M+1); 741.9 (M−1);morpholin-4-yl-1H-[1,2,3]triazol-4-yl]- TLC (50% Et₂O in hexane): R_(f)= 0.1. [5-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-(2-chloro-phenyl)-isoxazol-4- yl]-methanone 178[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 731.0 (M+1)⁺morpholin-4-yl-1H-[1,2,3]triazol-4-yl]- [5-(tert-butyl-dimethyl-silanyloxymethyl)-3-(3-chloro-pyridin-4- yl)-isoxazol-4-yl]-methanone179 [1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 731.1, 733.3 (M+1).morpholin-4-yl-1H-[1,2,3]triazol-4-yl]- [5-(tert-butyl-dimethyl-silanyloxymethyl)-3-(4-chloro-pyridin-3- yl)-isoxazol-4-yl]-methanone180 [1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 731.4, 733.4 (M+1)⁺;R_(f) = 0.73 morpholin-4-yl-1H-[1,2,3]triazol-4-yl]- (6.25%MeOH/CH₂Cl₂). [5-(tert-butyl-dimethyl-silanyloxymethyl)-3-(2-chloro-pyridin-3- yl)-isoxazol-4-yl]-methanone181 [1-(3,5-bis-trifluoromethyl-benzyl)-5- R_(f) = 0.23 (3:1 Hex/EtOAc);morpholin-4-yl-1H-[1,2,3]triazol-4-yl]- MS/ES (M+1) = 732.0[5-(tert-butyl-dimethyl- silanyloxymethyl)-3-(2,6-difluoro-phenyl)-isoxazol-4-yl]-methanone 182[1-(3,5-bis-trifluoromethyl-benzyl)-5- R_(f) = 0.24 (3:1 Hex/EtOAc);morpholin-4-yl-1H-[1,2,3]triazol-4-yl]- MS/ES (M+1) = 764.0[5-tert-butyl- dimethylsilanyloxymethyl)-3-(2,6-dichloro-phenyl)-isoxazol-4-yl]- methanone 183[1-(3,5-bis-trifluoromethyl-benzyl)-5- R_(f) = 0.53 (2:1 Hex/EtOAc);morpholin-4-yl-1H-[1,2,3]triazol-4-yl]- MS/ES (M+1): 716.3[5-(2-chloro-phenyl)- 3-(1-methyl-1-trimethylsilanyloxy-ethyl)-isoxazol-4-yl]-methanone 184[1-(3,5-bis-trifluoromethyl-benzyl)-5- TLC: R_(f) = 0.35 (1:2hexanes/EtOAc) morpholin-4-yl-1H-[1,2,3]triazol-4-yl]- MS (ES) 686.0(M+1), 629.8 [5-(1-tert-butoxy-ethyl)-3-(2-chloro- [(M—C(CH₃)₃)⁺]phenyl)-isoxazol-4-yl]-methanone 185[1-(3,5-bis-trifluoromethyl-benzyl)-5- m.p. 142–143° C.;morpholin-4-yl-1H-[1,2,3]triazol-4-yl]- TLC: R_(f) = 0.47 (2:1hexanes/EtOAc); [3-(2-chloro-phenyl)-5-(1-methyl-1- MS (ES) 715.9 (M+1),625.9 trimethylsilanyloxy-ethyl)-isoxazol-4- [(M—OSiMe₃)⁺] yl]-methanone

Preparation 1861-(3,5-bis-trifluoromethyl-benzyl)-4-(tri-n-butylstannanyl)-5-phenyl-1H-[1,2,3]triazole

Heat a mixture of tri-n-butyl-phenylethynyl-stannane (11.0 g, 30.0 mmol)and 3,5-bis-trifluoromethyl-benzyl azide (9.68 g, 36.0 mmol) in toluene(40 mL) at reflux until reaction is complete. Concentrate to remove thesolvent in vacuo and purify the residue by flash chromatography onsilica gel (elution with 17% ether in hexanes) to give the titlecompound (17.5 g, 26.4 mmol, 88%). MS (ES) 660.1, 662.1 (M+1); LC Rf=0.1(17% ether in hexanes).

Preparation 187 tert-Butoxycarbonylamino-acetic acid4-[1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazole-4-carbonyl]-3-(2-chloro-phenyl)-isoxazol-5-ylmethyl ester

Add TEA (124 mg, 1.22 mmol), EDCI (75 mg, 0.39 mmol) and DMAP (30 mg,0.24 mmol) to a solution of N-Boc glycine (68 mg, 0.39 mmol) and[1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazol-4-yl]-[3-(2-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-yl]-methanone(150 mg, 0.244 mmol) in CH₂Cl₂. Stir the mixture at RT until thereaction is complete. Dilute the reaction mixture with CH₂Cl₂ (100 mL)and wash with water (3×50 mL). Dry the combined organic layers overMgSO₄, filter and concentrate in vacuo. Purify by chromatography onsilica gel. MS (ES) 773.1 (M⁺+1); TLC R_(f)=0.2 (50% EtOAc in hexanes).

General Preparation M

Heat a mixture of the appropriate heteroaryl bromide (1.0 eq),ethynyl-trimethyl-silane (2.0 eq), PdCl₂(PPh₃)₂ (0.1 eq), CuI (0.2 eq)and diisopropyl ethyl amine (10 eq) in DMF at 70° C. After 18 h., dilutewith methylene chloride, and wash with water. Dry over MgSO₄, filter andconcentrate in vacuo. Purify the residue by flash chromatography onsilica gel to give the desired compound.

By the method of General Preparation M, using the appropriate startingmaterials, the following compound may be prepared and isolated.

Prep. # Product Physical Data 188 4-trimethyl- MS (ES) 176.0 (M+1); TLCR_(f) = 0.1 (20% silanylethynyl- ether in hexanes). pyridine 1892-trimethyl- ¹H NMR (300 MHz, CDCl₃) δ 8.65–8.71 silanylethynyl- (m,1H), 8.52–8.55 (m, 1H), 8.45–8.48 (m, pyrazine 1H), 0.30 (s, 9H).

Preparation 190 5-trimethylsilanylethynyl-pyrimidine

Dissolve 5-bromopyrimidine (50.0 g, 314.4 mmol) in triethylamine (400mL), add copper (1) iodide (1.20 g, 6.2 mmol) and stir mixture undernitrogen. After 15 min., add trimethylsilyl acetylene (53.3 mL, 377.3mmol), followed by dichlorobis(triphenyl-phosphine) palladium (11) (8.82g, 12.5 mmol) and stir at RT. After 3 h, filter the solution throughCelite®, rinsing with ether. Concentrate the filtrate under reducedpressure. Purification by flash chromatography on silica gel elutingfirst with hexanes (100%), then with hexanes:EtOAc (3:1) gives the titlecompound: ¹H NMR (300 MHz, CDCl₃) δ 9.10 (s, 1H), 8.77 (s, 2H), 0.27 (s,9H).

Preparation 191 4-ethynyl-pyridine

Add K₂CO₃ (3.32 g, 24.0 mmol) to a solution of4-trimethylsilanylethynyl-pyridine (3.51 g, 20.0 mmol) in MeOH (40 mL).After 10 min., add sat. aq. NH₄Cl solution (approx. 10 mL) and stir.After 10 min., add MgSO₄, filter and concentrate at RT. Purify byKugelrohr distillation (50–55° C.) to afford the title compound (1.31 g,64%). MS(ES) 104 (M+1). ¹H NMR (400 MHz, CDCl₃) δ 3.29 (s, 1H); 7.34 (d,2H, J=5.9 Hz); 8.59 (d, 2H, J=5.9 Hz).

Preparation 192 4-methyl-4-trimethylsilanyloxy-pent-2-ynal

Dissolve 3-methyl-3-trimethylsilyloxy-1-butyne (8.35 g, 53.4 mmol) inTHF (200 mL) and cool to 40° C. Add n-butyllithium (26.7 mL of a 2.0 Msolution in cyclohexane, 53.4 mmol, 1 eq.) dropwise over a 5 minuteperiod. Stir for 10 min., then add dry DMF (8.27 mL, 7.81 g, 107 mmol, 2eq.) in one portion. After 30 min., pour into a cooled (0° C.),vigorously stirred mixture of 10% KH₂PO₄ (290 mL, 213 mmol) and ether(300 mL). Separate the layers and wash the organic layer with water(2×200 mL). Dry (MgSO4), filter, and concentrate to give 9.4 g (94%crude) of a light oil. Use without further purification. TLC: R_(f)=0.40(20:1 hexanes/EtOAc); ¹H NMR (CDCl₃, 300 MHz) δ 9.03 (s, 1H), 1.35 (s,6H), 0.02 (s, 9H).

General Preparation N

Dissolve the alkyne (1.0 eq) in ether (0.25 M) and add triethylamine(2.4 eq.). Add 2-chloro-N-hydroxybenzenecarboximidoyl chloride (1.2 eq.)as a solution in ether (1 M) dropwise via an addition funnel over aperiod of 2 h. After 24 h, dilute with ether and wash with water (2×)and brine. Dry (MgSO₄), filter, and concentrate to give a yellow oil.Purify by crystallization from hexanes, or by chromatography (silicagel, hexanes/EtOAc gradient).

By the method of General Preparation N, the following compounds may beprepared and isolated.

Prep. # Product Physical Data 1933-(2-chloro-phenyl)-5-(tetrahydro-pyran- R_(f) = 0.63 (1:1 Hex/EtOAc);2-yloxymethyl)-isoxazole-4-carbaldehyde MS (ES) 322.1 (M+1). 1943-(2-chloro-phenyl)-5-(1-methyl-1- m.p. 88–90° C.;trimethylsilanyloxy-ethyl)-isoxazole-4- TLC: R_(f) = 0.29 (10:1 hexanes/carbaldehyde EtOAc); MS (ES) 338.2 (M+1), 248.0[(M—OSiMe₃)⁺].

Preparation 1955-(2-chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazole-4-carboxylicacid ethyl ester

Add 2-(2-nitroethoxy)tetrahydropyran (41 mL, 270 mmol) dropwise intoluene (100 mL) to a solution of (2-chloro-phenyl)-propynoic acid ethylester (28.3 g, 135 mmol), 1,4-phenylene diisocyanate (67 g, 420 mmol)and triethylamine (15 mL) in toluene (900 mL). Stir at reflux for 10 h.While still warm (˜70° C.), filter the reaction mixture through Celite®,washing the solids with EtOAc. Wash the filtrate with 1N HCl (500 mL)and brine (500 mL). Dry the organics over Na₂SO₄, filter and concentrateunder reduced pressure. Purification by flash chromatography (silicagel, 85:15 Hexanes/EtOAc) gives the title compound (46.5 g, 94%). MS(m/e): 282 (M−C₅H₈O+H⁺); ¹H NMR (300 MHz, CDCl₃) δ 7.35–7.55 (m, 4H),5.09 (d, J=13 Hz, 1), 4.85–4.91 (m, 2H), 4.15–4.22 (m, 2H), 3.91–4.01(m, 1H), 3.52–3.61 (m, 1H), 1.49–1.92 (m, 6H), 1.12 (t, J=7 Hz, 3H); TLCR_(f)=0.53 (7:3 Hexanes/EtOAc).

Preparation 1965-(2-chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazole-4-carboxylicacid methoxy-N-methyl-amide

Add 2M iso-propylmagnesium chloride (717 mL, 1.4 mol) to a −10° C.solution of5-(2-chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazole-4-carboxylicacid ethyl ester (175 g, 478 mmol) and N,O-dimethylhydroxylaminehydrochloride (56 g, 574 mmol) in THF (2 L). Stir the reaction for 45min. and then slowly quench with a 1:1 mixture of sat. NH₄Cl and water(750 mL). Extract the mixture with EtOAc (3×500 mL). Wash the organicphase with brine (1000 mL), dry over Na₂SO₄, filter, and concentrateunder reduced pressure. Purification by flash chromatography (silicagel, 7:3 hexanes/EtOAc) gives the title compound (27 g, 52%). MS (m/e):381 (M+H)⁺; m.p.=51–56° C.; ¹H NMR (300 MHz, CDCl₃) δ7.32–7.60 (m, 4H),5.00 (d, J=14 Hz, 1H), 4.78–4.81 (m, 1H), 4.73 (d, J=14 Hz, 1H),3.85–3.98 (m, 1H), 3.52–3.61 (m, 1H), 3.40 (s, 3H), 3.10–3.29 (m, 3H),1.50–1.82 (m, 6H); HPLC >99%; TLC R_(f)=0.41 (1:1 Hexanes/EtOAc).

Preparation 1971-[5-(2-chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-4-yl]-3-pyridin-4-yl-propynone

Add 2.5 M butyllithium (18.8 mL, 47 mmol) to a −10° C. solution of4-ethynyl pyridine (4.2 g, 40.7 mmol) in THF (100 mL). Stir thissolution for 15 min. and then add5-(2-chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazole-4-carboxylicacid methoxy-methyl-amide (5.0 g, 13.1 mmol) in THF (100 mL). Stir thereaction at RT 15 h and then quench with water (100 mL) and extract withEtOAc (2×150 mL). Wash the organics with brine (150 mL), dry (Na₂SO₄),filter and concentrate under reduced pressure. Purification by flashchromatography (silica gel, 7:3 to 1:1 hexanes/EtOAc) gives the titlecompound (4.5 g, 81%). MS (m/e): 423 (M+H⁺); ¹H NMR (300 MHz, CDCl₃)δ8.56 (d, J=5.8 Hz, 2H), 7.41–7.59 (m, 4H), 6.91 (d, J=5.8 Hz, 2H), 5.15(d, J=14 Hz, 1H), 4.90–4.96 (m, 2H), 3.94–4.01 (m, 1H), 3.51–3.62 (m,1H), 1.52–1.92 (m, 6H); TLC R_(f)=0.42 (9:1 EtOAc/Hexanes).

By a method analogous to Preparation 197, using the appropriate startingmaterials, the following compounds may be prepared and isolated.

Prep. # Product Physical Data 198 1-[5-(2-chloro-phenyl)-3-(tetrahydro-MS (m/e): 423 (M+H⁺); ¹H NMR (300 MHz,pyran-2-yloxymethyl)-isoxazol-4-yl]- CDCl₃) δ 8.57–8.59 (m, 1H), 8.12(s, 3-pyridin-3-yl-propynone 1H), 7.41–7.62 (m, 5H), 7.21–7.25 (m, 1H),5.15 (d, J = 14 Hz, 1H), 4.91–4.96 (m, 2H), 3.94–4.01 (m, 1H), 3.58–3.62(m, 1H), 1.54–1.86 (m, 6H); TLC R_(f) = 0.38 (7:3 EtOAc/Hexanes). 1991-[5-(2-chloro-phenyl)-3-(tetrahydro- MS (m/e): 304 (M−C₅H₈O+H⁺); ¹Hpyran-2-yloxymethyl)-isoxazol-4-yl]- NMR (300 MHz, CDCl₃) δ 7.40–7.57(m, 4-methyl-pent-2-yn-1-one 4H), 5.10 (d, J = 14 Hz, 1H), 4.87–4.93 (m,2H), 3.93–4.00 (m, 1H), 3.57–3.61 (m, 1H), 2.24–2.31 (m, 1H), 1.52–1.92(m, 6H), 0.87 (s, 3H), 0.85 (s, 3H); TLC R_(f) = 0.34 (4:1Hexanes/EtOAc). 200 1-[5-(2-chloro-phenyl)-3-(tetrahydro- MS (m/e): 360(M+H⁺); ¹H NMR (300 MHz, pyran-2-yloxymethyl)-isoxazol-4-yl]- CDCl₃) δ7.41–7.58 (m, 4H), 5.10 (d, but-2-yn-1-one J = 14 Hz, 1H), 4.88–4.93 (m,2H), 3.93–3.99 (m, 1H), 3.57–3.60 (m, 1H), 1.53–1.88 (m, 9H); HPLC>99%;TLC R_(f) = 0.53 (3:7 EtOAc/Hexanes). 2011-[5-(2-chloro-phenyl)-3-(tetrahydro- MS [ES] 422.1 (M+H)+.pyran-2-yloxymethyl)-isoxazol-4-yl]- 1H NMR (400 MHz, CHCl₃) δ 8.55 (m,3-pyridin-2-yl-propynone 1H), 7.58 (m, 2H), 7.44 (m, 1H), 7.37 (m, 2H),7.28 (m, 1H), 7.04 (dt, 1H, J = 7.8, 1.0 Hz), 5.16 (d, 1H, J = 13.8 Hz),4.96 (d, 1H, J = 13.8 Hz), 4.94 (m, 1H), 3.94–4.00 (m, 1H), 3.57–3.62(m, 1H), 1.53–1.91 (m, 6H).

Preparation 2021-[5-(2-chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-4-yl]-3-cyclopropyl-propynone

Cool THF (200 mL) to −10° C. under nitrogen and add a 2.5 M solution ofn-butyllithium in hexanes (56 mL, 140 mmol) dropwise, keeping thetemperature below 5° C. Add 5-chloropentyne (6.89 g, 67.2 mmol) at 5° C.and stir for 6 h. Add a solution of5-(2-chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazole-4-carboxylicacid methoxy-methyl-amide (8.5 g, 22.4 mmol) in THF (100 mL) dropwise tothe reaction mixture and stir for 30 min., not allowing the temperatureto rise above 10° C. Quench the reaction mixture with water (100 mL),extract with EtOAc (2×200 mL), wash with brine (200 mL), dry over sodiumsulfate, filter and concentrate under reduced pressure. Purification byflash chromatography, eluting with 4:1 hexanes:EtOAc to 7:3hexanes:EtOAc followed by reverse phase prep HPLC eluting withacetonitrile:water gives the title compound as a colorless oil (3.24 g,38%): MS (m/e): 386 (M+H⁺); ¹H NMR (300 MHz, CDCl₃) δ 7.38–7.54 (m, 4H),4.90–5.13 (m, 3H), 3.91–4.00 (m, 1H), 3.55–3.62 (m, 1H), 1.55–1.95 (m,6H), 0.92–1.02 (m, 1H), 0.71–0.77 (m, 2H), 0.37–0.46 (m, 2H); TLCR_(f)=0.43 (7:3 Hexanes:EtOAc).

Preparation 2035-(2-chloro-phenyl)-3-tetrahydro-pyran-2-yloxymethyl)-isoxazole-4-carbaldehyde

Add 1 M diisobutylaluminum hydride (316 mL, 316 mmol) dropwise to a −78°C. solution of5-(2-chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazole-4-carboxylicacid methoxy-methyl-amide (80 g, 211 mmol) in THF (1 L). Warm thereaction to RT and stir for 2 h. Quench the reaction with 1N HCl and addpotassium sodium tartrate tetrahydrate (30 g). Stir for 30 min. andextract with methylene chloride (2×600 mL). Wash the organic phase withbrine, dry over Na₂SO₄, filter and concentrate under reduced pressure togive the title compound (61.5 g, 90%): ¹H NMR (300 MHz, CDCl₃) δ 9.90(s, 1H), 7.41–7.62 (m, 4H), 5.12 (d, J=14 Hz, 1H), 4.88–4.96 (m, 2H),3.90–4.01 (m, 1H), 3.55–3.62 (m, 1H), 1.54–1.86 (m, 6H); TLC R_(f)=0.59(7:3 Hexanes:EtOAc).

Preparation 2041-[5-(2-chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-4-yl]-3-pyrimidin-5-yl-prop-2-yn-1-ol

Add 3M ethylmagnesium bromide (36 mL, 109 mmol) in diethyl ether to a 0°C. solution of 5-ethynyl-pyrimidine (8.1 g, 77 mmol) in THF (75 mL). Add5-(2-chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazole-4-carbaldehyde(10 g, 31 mmol) in THF (75 mL) and stir 15 h at RT. Quench the reactionwith 1N HCl and extract with diethyl ether (2×150 mL). Wash the organicphase with brine (150 mL), dry over sodium sulfate, filter andconcentrate under reduced pressure. Purification by flash chromatography(silica gel, 1:1 to 3:7 hexanes/EtOAc) gives the title compound (5.3 g,40%): ¹H NMR (300 MHz, CDCl₃) δ 9.18 (s, 1H), 8.35 (s, 2H), 7.44–7.62(m, 4H), 5.65 (t, J=14 Hz, 1H), 5.08–5.28 (m, 1H), 4.80–4.95 (m, 2H),4.42–4.60 (m, 1H), 3.80–4.01 (m, 1H), 3.51–3.68 (m, 1H), 1.54–1.90 (m,6H); TLC R_(f)=0.20 (3:7 Hexanes:EtOAc).

Preparation 2051-[3-(2-chloro-phenyl)-5-(1-methyl-1-trimethylsilanyloxy-ethyl)-isoxazol-4-yl]-3-pyridin-3-yl-prop-2-yn-1-ol

Dissolve 3-ethynylpyridine (206 mg, 2.0 mmol, 2 eq.) in THF (3 mL). Coolto 0° C. and add LDA (1.47 mL of a 1.5 M soln. in THF, 2.2 mmol, 2.2eq.) dropwise. After 30 min., add3-(2-chloro-phenyl)-5-(1-methyl-1-trimethylsilanyloxy-ethyl)-isoxazole-4-carbaldehyde(340 mg, 1.0 mmol) as a solution in THF (2 mL). Warm the mixture to RT.After 45 min., quench with 10% KH₂PO₄ (10 mL). Extract with EtOAc (2×15mL), and wash the combined organic layers with brine (15 mL). Dry(MgSO₄), filter, and concentrate. Purify by chromatography (silica gel,hexanes/EtOAc 2:1 to 1:1 gradient) to provide 370 mg (84%) alcohol as anoil. TLC: R_(f)=0.33 (2:1 hexanes/EtOAc); MS(ES) 441.2 (M+1)⁺.

Using a method similar to Preparation 205, with the appropriate startingmaterials, the following compound may be prepared.

Prep. # Product Physical Data 206 1-[3-(2-chloro-phenyl)-5-(tetrahydro-R_(f) = 0.09 2:1 Hex/EtOAc pyran-2-yloxymethyl)-isoxazol-4-yl]-3- MS(ES) 425.1 (M+1) pyridin-3-yl-prop-2-yn-1-ol

General Preparation O

To the alcohol of interest (1 eq) in toluene, add MnO₂ (10 eq). Heat thereaction at 110° C. for 18 h. Cool the mixture to RT, add Celite®, andfilter. Concentrate the filtrate and purify the residue bychromatography on silica gel (hexanes/EtOAc gradient) to afford thetitle compound.

Using the method of General Preparation O, the following compounds maybe prepared and isolated.

Prep. # Product Physical Data 207 1-[3-(2-chloro-phenyl)-5-(tetrahydro-R_(f) = 0.19 (1:1 Hex/EtOAc); pyran-2-yloxymethyl)-isoxazol-4-yl]-3- MS(ES) 423.1 (M+1)⁺ pyridin-3-yl-propynone 2081-[3-(2-chloro-phenyl)-5-(1-methyl-1- TLC: R_(f) = 0.44 (2:1hexanes/EtOAc); trimethylsilanyloxy-ethyl)-isoxazol-4- MS (ES) 439.1(M+1)⁺ yl]-3-pyridin-3-yl-propynone 2091-[5-(2-chloro-phenyl)-3-(tetrahydro- MS (m/e): 340 (M−C₅H₈O+H⁺); ¹Hpyran-2-yloxymethyl)-isoxazol-4-yl]-3- NMR (300 MHz, CDCl₃) δ 9.18 (s,1H), pyrimidin-5-yl-propynone 8.35 (s, 2H), 7.44–7.62 (m, 4H), 5.15 (d,J = 14 Hz, 1H), 4.90–495 (m, 2H), 3.94–4.00 (m, 1H), 3.58–3.62 (m, 1H),1.54–1.85 (m, 6H); TLC R_(f) = 0.53 (7:3 EtOAc/Hexanes).

General Preparation P

To a solution of the THP-protected alcohol (1 eq) in THF/H₂O (1:1, 0.20M) add an equal volume of glacial acetic acid. Heat solution at 60° C.for 18 h. Cool reaction to 0° C. and dilute with H₂O. Add 5N NaOH untilreaction is basic, and extract with CH₂Cl₂, wash the organic layer withbrine, dry over MgSO₄, and concentrate. Recrystallize the product fromHex/EtOAc (two crops). Dry crystals to afford the title compound.

Using the above method and the appropriate starting materials, thefollowing compounds may be prepared.

Prep. # Product Physical Data 210 1-[5-(2-chloro-phenyl)-3- R_(f) = 0.25(3:1 Hex/EtOAc); hydroxymethyl-isoxazol-4-yl]-4- MS (ES) 304.1 (M+1)methyl-pent-2-yn-1-one 211 1-[5-(2-chloro-phenyl)-3- R_(f) = 0.24 (2:1Hex/EtOAc); hydroxymethyl-isoxazol-4-yl]-but- MS (ES) 276.0 (M+1)2-yn-1-one

General Preparation Q

To a solution of the appropriate alkyne (1 eq) in toluene (0.25 M) addthe azide of interest (2 eq). Heat the mixture at 120° C. for 18 h in asealed tube, then cool to r.t. and concentrate. Purify the residue bychromatography on silica gel to yield title compound.

Using the procedure above and the appropriate alkynes and azides, thefollowing compounds may be prepared.

Prep. # Product Physical Data 212[3-(2-chloro-phenyl)-5-(tetrahydro-pyran-2- R_(f) = 0.38 (1:1Hex/EtOAc); yloxymethyl)-isoxazol-4-yl]-[1-(3,5- MS (ES) 624.0, 626.0(M+1). dichloro-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-methanone 213[3-(2-chloro-phenyl)-5-(tetrahydro-pyran-2- R_(f) = 0.55 (1:2Hex/EtOAc); yloxymethyl)-isoxazol-4-yl]-[5-pyridin-3-yl- MS (ES) 640.1(M+1). 1-(3-trifluoromethoxy-benzyl)-1H- [1,2,3]triazol-4-yl]-methanone214 [3-(2-chloro-phenyl)-5-(tetrahydro-pyran-2- R_(f) = 0.54 (1:2Hex/EtOAc); yloxymethyl)-isoxazol-4-yl]-[1-(3,5- MS (ES) 584.2 (M+1).dimethyl-benzyl)-5-pyridin-3-yl-1H- [1,2,3]triazol-4-yl]-methanone 215[3-(2-Chloro-phenyl)-5-(tetrahydro-pyran-2- Rf = 0.31 (1:2 Hex/EtOAc)yloxymethyl)-isoxazol-4-yl]-[1-(2-fluoro-5- MS (ES) 642.1 (M+1)trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-methanone 216[3-(2-Chloro-phenyl)-5-(tetrahydro-pyran-2- Rf = 0.62 (1:2 Hex/EtOAc)yloxymethyl)-isoxazol-4-yl]-[1-(2-methoxy- MS (ES) 670.1 (M+1)5-trifluoromethoxy-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-methanone

General Preparation R

Add the appropriate sodium carboxylate (2 eq.) to a solution of2-bromo-1-(2-chloro-phenyl)-ethanone (1 eq.) in DMF (0.8M). Stir mixtureat RT overnight, then dilute with water and brine and extract withether. Combine the organic layers and wash with 20% Na₂SO₃ (50 mL) andbrine (50 mL), then dry, filter, and concentrate to give the product.

Alternatively, add sodium hydride (1.6 eq.) to a solution of theappropriate carboxylic acid (1.7 eq.) in DMF (0.5M). Stir mixture at RTfor 1 h., then add 2-bromo-1-(2-chloro-phenyl)-ethanone (1 eq.). Stirsolution at RT overnight. Add water and brine, then extract with ether.Combine the organic layers and wash with water, and brine, then dry,filter and concentrate. Purify the crude material by flashchromatography.

Using one of the above methods and the appropriate starting materials,the following compounds may be prepared and isolated.

Prep. # Product Physical Data 217 acetic acid 2- MS (ES+) 213.0 (M+1);(2-chloro-phenyl)- ¹H NMR (400 MHz, CDCl₃) δ 7.60 (m, 2-oxo-ethyl ester1H), 7.43 (m, 2H), 7.34 (m, 1H), 5.18 (s, 2H), 2.16 (s, 3H). 218isobutyric acid 2- MS (ES+) 241.0 (M+1); (2-chloro-phenyl)- ¹H NMR (400MHz, 2-oxo-ethyl ester CDCl₃) δ 7.57 (m, 1H), 7.41 (m, 2H), 7.33 (m,1H), 5.14 (s, 2H), 2.64 (m, 1H), 1.16 (d, 6H, J = 7.3 Hz). 219cyclopropane- MS (ES+) 239.1 (M+H)⁺; carboxylic acid ¹H NMR (400 MHz,CDCl₃) δ 7.60 (m, 2-(2-chloro-phenyl)-2- 1H), 7.43 (m, 2H), 7.34 (m,1H), 5.18 oxo-ethyl ester (s, 2H), 1.73 (m, 1H), 1.05 (m, 2H), 0.93 (m,2H).

General Preparation S

Add BF₃.OEt₂ (0.5 eq.) to a mixture of acetamide (5.2 eq.) and theappropriate ester (1 eq.). Warm mixture to 130° C. for 4 h., then coolto RT. Add saturated NaHCO₃ or 20% Na₂CO₃ solution, and extract withether. Combine the organic layers and wash with brine, then dry, filter,and concentrate to give the crude material. Purify by flashchromatography. The above method may be used to prepare the followingcompounds.

Prep. # Product Physical Data 220 4-(2-chloro- MS (ES+) 194.0 (M+1);phenyl)-2- ¹H NMR (400 MHz, CDCl₃) δ 8.22 (s, 1H), methyl-oxazole 8.07(dd, 1H, J = 1.5, 7.8 Hz), 7.41 (dd, 1H, J = 1.0, 7.8 Hz), 7.32 (dt, 1H,J = 1.0, 7.8 Hz), 7.21 (dt, 1H, J = 1.5, 7.8 Hz), 2.51 (s, 3H). 2214-(2-chloro- MS (ES+) 222.0 (M+1); phenyl)-2- ¹H NMR (400 MHz, CDCl₃) δ8.22 (s, 1H), isopropyl- 8.11 (dd, 1H, J = 2.0, 7.8 Hz), 7.41 (dd, 1H,oxazole J = 1.5, 7.8 Hz), 7.32 (dt, 1H, J = 1.5, 7.8 Hz), 7.20 (dt, 1H,J = 2.0, 7.8 Hz), 3.14 (septet, 1H, J = 7.3 Hz), 1.38 (d, 6H, J = 7.3Hz). 222 4-(2-chloro- MS (ES+) 220.1 (M+H); phenyl)-2- ¹H NMR (400 MHz,CDCl₃) δ 8.16 (s, 1H), cyclopropyl- 8.09 (dd, 1H, J = 7.8, 1.4), 7.42(dd, 1H, J = oxazole 7.8, 1.4), 7.33 (dt, 1H, J = 7.8, 1.4), 7.21 (dt,1H, J = 7.8, 1.4), 2.13 (m, 1H), 1.12–1.15 (m, 2H), 1.03–1.10 (m, 2H).

General Preparation T

To a solution of the appropriate oxazole (1 eq.) in CCl₄ (1 M), addfreshly recrystallized NBS (1.1 eq.) and (PhCO)₂O₂ (5 mg). Stir mixtureat RT for 18–24 h, then filter through a pad of Celite® and concentratethe filtrate. Purify the crude material by flash chromatography. Thefollowing compounds may be prepared and isolated using the method ofGeneral Preparation T.

Prep. # Product Physical Data 223 5-bromo-4-(2- MS (ES+) 271.9, 273.9(M+1); chloro-phenyl)- ¹H NMR (400 MHz, CDCl₃) δ 7.44 (m, 2H),2-methyl-oxazole 7.31 (m, 2H), 2.51 (s, 3H). 224 5-bromo-4-(2- MS (ES+)300.0, 302.0 (M+1); chloro-phenyl)-2- ¹H NMR (400 MHz, CDCl₃) δ 7.44 (m,2H), isopropyl-oxazole 7.30 (m, 2H), 3.12 (septet, 1H, J = 6.8 Hz), 1.38(d, 6H, J = 6.8 Hz). 225 5-bromo-4-(2- MS (ES+) 298.0, 300.0 (M+2);chloro-phenyl)-2- ¹H NMR (400 MHz, CDCl₃) δ 7.44 (m, 2H), cyclopropyl-7.32 (m, 2H), 2.11 (m, 1H), 1.05–1.17 oxazole (m, 4H).

General Preparation U

Add Mg turnings (1.2 eq.) and a small crystal of iodine to a solution ofthe appropriate 5-bromo-oxazole (1 eq.) in freshly distilled THF (0.2M). Stir the mixture at reflux for 14 h., then cool to RT. Add viacannula a solution of desired carbaldehyde (0.8 eq.) in THF (0.3 M).Stir the solution at RT for 2–18 h. Dilute solution with water and addsaturated NaHCO₃ or 1N HCl, then extract with EtOAc. Combine the organiclayers and wash with aqueous saturated NaHCO₃ and brine, then dry,filter, and concentrate. Purify the crude material by flashchromatography.

Alternatively, add t-BuLi (2 eq.) to a −78° C. solution of theappropriate 5-bromo-oxazole (1 eq.) in THF (0.9 M). Stir solution at−78° C. for 15 min., then add via cannula a solution of desiredcarbaldehyde (0.9 eq.) in THF (0.2 M). Stir the solution at −78° C. for30 min., then at RT for 60 h. Dilute the solution with EtOAc and washwith NaHCO₃ and brine, then dry, filter, and concentrate the organicphase. Purify the crude material by flash chromatography.

Using one of the methods described above, the following compounds may beprepared and isolated.

Prep. # Product Physical Data 226 [1-(3,5-bis-trifluoromethyl-benzyl)-5-MS (ES+) 593.9 (M+1), MS (ES−) pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-[4-591.9 (M−1). (2-chloro-phenyl)-2-methyl-oxazol-5-yl]- methanol 227[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES+) 551.1 (M+1), MS (ES−)chloro-1H-[1,2,3]triazol-4-yl]-[4-(2- 549.1 (M−1).chloro-phenyl)-2-methyl-oxazol-5-yl]- methanol 228[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES+) 579.0 (M+1)⁺, MS (ES−)chloro-1H-[1,2,3]triazol-4-yl]-[4-(2- 577.0 (M−1)⁻. ¹H NMR (400 MHz,chloro-phenyl)-2-isopropyl-oxazol-5-yl]- CDCl₃) δ 7.86 (s, 1H), methanol7.73 (s, 2H), 7.34 (m, 2H), 7.20 (m, 2H), 5.96 (d, 1H, J = 5.9 Hz), 5.52(s, 2H), 3.52 (d, 1H, J = 5.9 Hz), 3.07 (sept., 1H, J = 7.3 Hz), 1.31(d, 3H, J = 6.8 Hz), 1.30 (d, 3H, J = 7.3 Hz). 229[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES+) 577.1 (M+H)+.chloro-1H-[1,2,3]triazol-4-yl]-[4-(2- ¹H NMR (400 MHz, CDCl₃) δ 7.89 (s,1H), chloro-phenyl)-2-cyclopropyl-oxazol-5- 7.77 (s, 2H), 7.37 (m, 2H),7.25 (m, 2H), yl]-methanol 5.95 (d, 1H, J = 6.6 Hz), 5.55 (s, 2H), 3.13(d, 1H, J = 6.6 Hz), 2.08 (m, 1H), 1.15 (m, 2H), 1.06 (m, 2H).

Preparation 2301-(3,5-bis-trifluoromethyl-benzyl)₄-ethynyl-5-phenyl-1H-[1,2,3]triazole

To sodium hydride (188 mg of a 60% solution in mineral oil, 113 mgclean, 4.70 mmol) in 14 mL of benzene and 2.5 mL of tetrahydrofuran, add(2-oxo-propyl)-phosphonic acid dimethyl ester (743 mg, 618 μL, 4.48mmol) as a solution in 5 mL of benzene at 0° C. dropwise. The mixremains white and produces some gas. After 1 h at 0° C., add tosyl azide(940 mg, 4.70 mmol) as a solution in 2.5 mL of benzene and warm themixture to RT. After 2.3 hours, pour the mix through a plug of Celite®rinsing with tetrahydrofuran, benzene, and ether. Concentrate thefiltrate and purify the residue by chromatography (Hexanes/EtOAcgradient) to provide 794 mg of (1-Diazo-2-oxo-propyl)-phosphonic aciddimethyl ester as a yellow solid. This material may be used directly.Exact Mass 192.03: mass spectrum (aspci): m/z=165.0 (M+1 (—N₂).

To the (1-Diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (794 mg,4.20 mmol) in 70 mL of methanol, add1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carbaldehyde(1.44 g, 3.60 mmol) as a solution in 5 mL of methanol. To this mix, add(995 mg, 7.20 mmol) of potassium carbonate and mix the solution for 18h. Dilute with ether and saturated NaHCO₃, and extract with ether 3times, wash the organics again with saturated NaHCO₃, and dry thecombined organics with MgSO₄. Filter and concentrate. Purify bychromatography (silica gel, hexanes/EtOAc gradient) to provide 764 mg ofthe title compound. Exact Mass 395.09 spectrum (aspci): m/z=396.1 (M+1),394.0 (M−1); ¹H NMR (250 MHz, CDCl₃) δ 7.73 (s, 1H), 7.55–7.40 (m, 4H),7.42–7.30 (m, 3H), 5.52 (s, 2H), 3.21 (s, H).

By a method analogous to Preparation 230, the following compounds may beprepared and isolated.

Prep. # Product Physical Data 231 4-[3-(3,5-bis-trifluoromethyl- ExactMass 396.08 spectrum (aspci): benzyl)-5-ethynyl-3H- m/z = 397.1 (M+1),395.1 (M−1); ¹H NMR (250 MHz, [1,2,3]triazol-4-yl]-pyridine CDCl₃) δ8.72 (d, J = 6.0 Hz, 2H), 7.77 (s, 1H), 7.48 (s, 2H), 7.22 (d, J = 6.0Hz, 2H), 5.64 (s, 2H), 3.22 (s, 1H).

General Preparation V

Dissolve the appropriate alkyne (9.76 mmol) in THF (50 mL) and cool to−78° C. Add a solution of MeMgBr (3eq, 3.0M in ether) and stir at −78°C. for 1.5 hours, then add 2-chlorobenzaldehyde (3eq). Stir solution at−78° C. for 1 hour, then at RT for 2 hours. Dilute the solution withether (100 mL) and wash with 1N HCl (30 mL), saturated NaHCO₃ (50 mL),and brine (50 mL). Dry, filter, and concentrate the organic phase thenpurify the crude material by flash chromatography (silica gel,hexanes/EtOAc gradient) to give the title compound.

By a method similar to General Preparation V, the following compoundsmay be prepared and isolated.

Prep # Product Physical Data 232 3-[1-(3,5-bis-trifluoromethyl-benzyl)-MS (ES) 536.0 (M+1); ¹H NMR (250 MHz,5-phenyl-1H-[1,2,3]triazol-4-yl]-1-(2- CDCl₃) δ 7.71 (s, 1H), 7.56 (m,1H), 7.43 (s, chloro-phenyl)-prop-2-yn-1-ol 2H), 7.35–7.48 (m, 3H),7.09–7.34 (m, 5H), 5.90 (s, 1H), 5.57 (s, 2H). 2333-[1-(3,5-bis-trifluoromethyl-benzyl)- MS (ES) 537.0 (M+1) 535.0 (M−1);5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]- ¹H NMR (250 MHz, CDCl₃) δ 8.65(d, J = 6.25 1-(2-chloro-phenyl)-prop-2-yn-1-ol Hz, 2H), 7.77 (s, 1H),7.60 (m, 1H), 7.48 (s, 2H), 7.10–7.35 (m, 5H), 5.92 (s, 1H), 5.63 (s,2H).

General Preparation W

Under N₂, charge an oven-dried flask with oxalyl chloride (2M in CH₂Cl₂,1.2 eq) and chill in a dry ice/acetone slush. Add DMSO (3 eq) slowly bysyringe and stir 45 minutes. Add the alcohol of interest (1 eq) inanhydrous CH₂Cl₂ (0.4 M) slowly by syringe and stir 1 hour. Add TEA (5eq) slowly by syringe and stir 90 minutes while warming to room temp.Quench with saturated aqueous NH₄Cl and H₂O, extract with ether, washcombined organics with brine, dry over MgSO₄, filter and concentrateunder vacuum. Purify by flash chromatography (silica gel, EtOAc/Hexanegradient) to give the title compound.

By a method similar to General Preparation W, the following compoundsmay be prepared and isolated.

Prep. # Product Physical Data 2343-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 534.0 (M+1), ¹H NMR(CDCl3): phenyl-1H-[1,2,3]triazol-4-yl]-1-(2- δ 8.03 (m, 1H), 7.86 (s,1H), chloro-phenyl)-propynone 7.63–7.30 (m, 10H), 5.70 (s, 2H) 2353-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 534.9 (M+1), ¹H NMR(300 MHz, pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-1- CDCl3): δ 8.86 (d, J =6.0 Hz, 2H), (2-chloro-phenyl)-propynone 8.02 (ap d, 1H), 7.90 (s, 1H),7.60 (s, 2H), 7.56–7.31 (m, 5H), 5.74 (s, 2H).

General Preparation X

Combine the alkyne of interest (1 eq) in benzene or toluene (0.1 M),with the appropriate nitro compound (1.5 eq), 1,4-phenylene diisocyanate(3 eq) and TEA (10 drops/mmol A). Attach a reflux condensor and heat toreflux. After 20 hours, add additional nitro compound (0.5 eq),1,4-phenylene diisocyanate (1 eq) and TEA, stir 6 hours. Remove fromheat, add H₂O and stir 20 min. Filter through Celite®, remove H₂O, dryover MgSO₄, filter and concentrate under vacuum. Purify bychromatography on silica gel to give the title compound.

By a method similar to General Preparation X, the following compoundsmay be prepared and isolated.

Prep. # Product Physical Data 236[5-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 691.9 (M+1), 607.8 (M− C₅H₈O) + pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-3- H⁺); TLC (3%(tetrahydro-pyran-2-yloxymethyl)- MeOH/CH₂Cl₂), Rf = 0.53.isoxazol-4-yl]-(2-chloro-phenyl)- methanone 237[5-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 689.0 (M−1); TLC (30%phenyl-1H-[1,2,3]triazol-4-yl]-3- EtOAc/Hexane × 2), Rf = 0.30.(tetrahydro-pyran-2-yloxymethyl)- isoxazol-4-yl]-(2-chloro-phenyl)-methanone 238 [5-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 665.9(M+1); pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-3-(2,2- TLC (30%EtOAc/Hexane), Rf = 0.16. dimethoxy-ethyl)-isoxazol-4-yl]-(2-chloro-phenyl)-methanone 239 [5-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES)665.9 (M+1); phenyl-1H-[1,2,3]triazol-4-yl]-3-(2,2- TLC (30%EtOAc/Hexane), Rf = 0.42. dimethoxy-ethyl)-isoxazol-4-yl]-(2-chloro-phenyl)-methanone

General Preparation Y

Dilute the THP-protected alcohol of interest (1 eq) in a solution ofacetic acid/H₂O/THF (2/1/1). Attach a reflux condensor, place in 60° C.bath, and stir 24 hours. Purify chromatography on silica gel to give thetitle compound.

Using a method similar to General Preparation Y, with the appropriatestarting material, the title compounds are prepared and isolated.

Prep. # Product Physical Data 240 {5-[1-(3,5-bis-trifluoromethyl- MS(ES) 607.0 (M+1), ¹H NMR (CDCl₃): δ benzyl)-5-phenyl-1H- 7.88 (s, 1H),7.63–7.46 (m, 4H), 7.41 (s, 2H), [1,2,3]triazol-4-yl]-3- 7.29–7.08 (m,5H), 5.46 (s, 2H), 4.87 (d, J = 7.3 hydroxymethyl-isoxazol-4-yl}-(2- Hz,2H), 3.86 (t, J = 7.3 Hz, 1H) chloro-phenyl)-methanone 241{5-[1-(3,5-bis-trifluoromethyl- MS (ES) 607.9 (M+1), ¹H NMR (CDCl₃): δbenzyl)-5-pyridin-4-yl-1H- 8.78 (dd, J = 4.3, 1.8 Hz, 2H), 7.89 (s, 1H),7.53 [1,2,3]triazol-4-yl]-3- (dd, J = 7.6, 2.2 Hz, 1H), 7.43 (s, 2H),7.33–7.27 hydroxymethyl-isoxazol-4-yl}-(2- (m, 2H), 7.12 (dd, J = 4.5,1.8 Hz, 2H), 7.07 (dd, chloro-phenyl)-methanone J = 7.6, 1.9 Hz, 1H),5.46 (s, 2H), 4.85 (s, 2H).

General Preparation Z

Under N₂, charge an oven-dried flask with oxalyl chloride (2M in CH₂Cl₂,1.2 eq) and chill in a dry ice/acetone slush. Add DMSO (3 eq) slowly bysyringe and stir 15 minutes. Add the hydroxymethyl isoxazole of interest(1 eq) in anhydrous CH₂Cl₂ (0.4 M) slowly by syringe and stir 1 hour.Add TEA (5 eq) slowly by syringe and stir 2 hours and allow to warm toRT. Quench with H₂O, extract with ether, dry over MgSO₄, filter andconcentrate under vacuum.

By using a method similar to General Preparation Z, the followingcompounds are prepared and isolated.

Prep. # Product Physical Data 242 5-[1-(3,5-bis-trifluoromethyl- ¹H NMR(CDCl₃): δ 10.11 (s, 1H), 8.78 (ap d, benzyl)-5-pyridin-4-yl-1H- 2H).7.86 (s, 1H), 7.75 (dd, J = 7.5, 1.8 Hz, 1H),[1,2,3]triazol-4-yl]-4-(2-chloro- 7.45–6.88 (m, 7H), 5.54 (s, 2H).benzoyl)-isoxazole-3- carbaldehyde 243 5-[1-(3,5-bis-trifluoromethyl- MS(ES) 605.1 (M+1), ¹H NMR (CDCl₃): δ benzyl)-5-phenyl-1H- 10.06 (s, 1H),7.75 (s, 1H), 7.63 (dd, J = 7.5, 1.8 [1,2,3]triazol-4-yl]-4-(2-chloro-Hz, 1H), 7.48–6.97 (m, 10H), 5.43 (s, 2H). benzoyl)-isoxazole-3-carbaldehyde

Preparation 244[5-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]4-(2-chloro-benzoyl)-isoxazol-3-yl]-acetaldehyde

Combine[5-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-3-(2,2-dimethoxy-ethyl)-isoxazol-4-yl]-(2-chloro-phenyl)-methanone(1 eq) in acetone/H₂O (4:1) and p-toluenesulfonic acid (1 eq) withstirring. Attach a reflux condensor and stir overnight in a 60° C. oilbath. Neutralize with saturated aqueous NaHCO₃, extract with ethylacetate, dry over MgSO₄, filter, and concentrate under vacuum. ¹H NMR(CDCl₃): δ 9.84 (s, 1H), 7.83 (s, 1H), 7.56–7.09 (m, 11H), 5.43 (s, 2H),4.09 (s, 2H).

By a method similar to Preparation 244, using the appropriate startingmaterials, the following compound may be prepared and isolated.

Prep. # Product Physical Data 245 [5-[1-(3,5-bis-trifluoromethyl- ¹H NMR(CDCl₃): δ 9.84 (s, 1H), 8.78 (app benzyl)-5-pyridin-4-yl-1H- t, 2H),7.87 (br s, 2H), 7.59–7.06 (m, [1,2,3]triazol-4-yl]-4-(2-chloro- 7H),5.46 (s, 2H), 4.10 (s, 2H) benzoyl)-isoxazol-3-yl]-acetaldehyde

General Preparation AA

Combine the appropriate keto-aldehyde (1 eq) in AcOH, then add hydrazine(1–3 eq) and stir at 25–80° C. After 1–4 hours, concentrate the solutionand dissolve the crude material in EtOAc and wash with saturated NaHCO₃and brine. Dry, filter, and concentrate the organic phase and purify thecrude material by flash chromatography (silica gel) to give the titlecompound.

Using the method of General Preparation AA, with the appropriatestarting materials, the title compounds are prepared and isolated.

Prep # Product Physical Data 2463-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 601.1 (M+1), ¹H NMR(CDCl₃): phenyl-1H-[1,2,3]triazol-4-yl]-4-(2- δ 9.59 (s, 1H), 7.87 (s,1H), 7.75–7.15 chloro-phenyl)-isoxazolo[3,4- (m, 11H), 5.56 (s, 2H).d]pyridazine 247 3-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES) 601.9(M+1), TLC Rf 0.15 (50% pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-4-(2-EtOAc/Hexane × 2). chloro-phenyl)-isoxazolo[3,4- d]pyridazine

General Preparation BB

Dissolve the appropriate keto-aldehyde (1 eq.) in acetic acid (0.15 M),add ammonium acetate (5 eq.), and stir at 65° C. for 90 min. Remove theacetic acid under reduced pressure, and neutralize the residue withsaturated aqeous NaHCO₃. Extract with ether, dry over MgSO₄, filter, andconcentrate under vacuum. Purify by chromatography on silica gel(Hexanes/EtOAc gradient) to give the desired compounds.

By using the method of General Preparation BB, using the appropriatestarting materials, the title compounds can be prepared and isolated.

Prep# Product Physical Data 248 3-[1-(3,5-bis-trifluoromethyl-benzyl)-5-MS (ES) 599.9 (M+1), ¹H NMR phenyl-1H-[1,2,3]triazol-4-yl]-4-(2-(CDCl₃): δ 8.35 (d, J = 6.5 Hz, 1H),chloro-phenyl)-isoxazolo[4,3-c]pyridine 7.84 (s, 1H), 7.58–7.13 (m,12H), 5.52 (s, 2H). 249 3-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS (ES)600.9 (M+1), ¹H NMR pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-4-(2- (CDCl₃):δ 8.76 (br s, 2H), 8.38 chloro-phenyl)-isoxazolo[4,3-c]pyridine (d, J =6.7 Hz, 1H), 7.89 (s, 1H), 7.60–7.36 (m, 6H), 7.12 (m, 3H), 5.56 (ap d,2H).

Preparation 2505-Amino-1-(3,5-bis-trifluoromethyl-benzyl)-1H-imidazole-4-carboxylicacid amide

Wash sodium hydride (2.71 g of a 60% solution in mineral oil, 67.66mmol) three times with hexanes, then dilute with 85 mL of DMF. To thismixture add the HCl salt of 5-amino-1H-imidazole-4-carboxylic acid amide(5.0 g, 30.75 mmol) neat in four portions. The mixture generates gas andremains cloudy and turns a slightly green color. After mixing for 40min., add 1-chloromethyl-3,5-bis-trifluoromethyl-benzene (8.88 g, 33.83mmol). (The mixture again generates gas and darkens). Stir at RT for 2days, then pour through a plug of Celite and wash with DMF (50 mL) andxylenes (50 mL). Remove the DMF via azeotropic distillation with xylenesunder reduced pressure (5×50 mL), and then concentrate the residue undera steady stream of nitrogen for 18 h to provide the title compound as adark purple solid. MS (ES) 351.1, 353.1 (M+1); ¹H NMR (300 MHz, CDCl₃) δ7.70 (s, 1H), 7.58 (s, 2H), 7.31 (s, 2H), 6.96 (s, 1H), 5.46 (s, 2H),5.10 (s, 2H).

Preparation 2515-Amino-1-(3,5-bis-trifluoromethyl-benzyl)-1H-imidazole-4-carbonitrile

Combine5-Amino-1-(3,5-bis-trifluoromethyl-benzyl)-1H-imidazole-4-carboxylicacid amide (0.106 g, 0.30 mmol) and p-toluenesulfonyl chloride (0.069 g,0.36 mmol) in pyridine (0.1 M), and stir at RT. After 2 h, quench thereaction with MeOH and concentrate. Redissolve in EtOAc, wash with H₂Oand brine, then dry (MgSO₄), filter, and concentrate. Purify by radialchromatography on silica gel to give the title compound. MS (ES) 335.1(M+1); ¹H NMR (300 MHz, CD₃OD): δ 7.96 (s, 1H), 7.77 (s, 2H), 7.37 (s,1H), 5.31 (s, 2H).

Preparation 2521-(3,5-Bis-trifluoromethyl-benzyl)-5-iodo-1H-imidazole-4-carbonitrile

Combine5-Amino-1-(3,5-bis-trifluoromethyl-benzyl)-1H-imidazole-4-carbonitrile(0.066 g, 0.20 mmol), CH₂I₂ (3 mL), and isoamyl nitrite (250 μL, 2 mmol)in a round bottom flask and stir the mixture at 100° C. After 30 min.,remove from heat and concentrate. Purify by flash chromatography onsilica gel to give the title compound. MS (ES) 443.9 (M−1); ¹H NMR (300MHz, CDCl₃) δ 7.93 (s, 1H), 7.78 (s, 1H), 7.58 (s, 2H), 5.31 (s, 2H).

Preparation 2531-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-imidazole-4-carbonitrile

In a pressure vessel dissolve1-(3,5-Bis-trifluoromethyl-benzyl)-5-iodo-1H-imidazole-4-carbonitrile(0.52 g, 1.2 mmol) in acetonitrile. Add 3-tributylstannanyl-pyridine(0.64 g, 1.7 mmol) and bis(benzonitrile)dichloropalladium(II) (22 mg,0.06 mmol), and stir at 100° C. After 72 h, quench with sat. aq. NaHCO₃,and extract with ether. Wash the organic layer with brine, dry overMgSO₄, filter, and concentrate. Purify by radial chromatography onsilica gel to give the title compound: MS (ES) 397.2 (M+1); ¹H NMR (300MHz, CDCl₃) δ 8.75 (d, J=4.6 Hz, 1H), 8.60 (ap d, 1H), 7.84 (s, 1H),7.75 (s, 1H), 7.66 (m, 1H), 7.44 (m, 1H), 7.36 (s, 2H), 5.30 (s, 2H).

Preparation 2541-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-imidazole-4-carboxylicacid methyl ester

In a pressure vessel dissolve1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-imidazole-4-carbonitrile(0.043 g, 0.11 mmol) in MeOH (1 mL), add H₂O (0.1 mL), and concentratedsulfuric acid (0.3 mL), and stir at 100° C. After 24 h., neutralize withsat. aq. NaHCO₃, and extract with EtOAc (3×). Dry over MgSO₄, filter,and concentrate. Purify by radial chromatography on silica gel to givethe title compound: MS (ES) 430.2 (M+1); ¹H NMR (300 MHz, CDCl₃): δ 8.68(ap d, 1H), 8.52 (ap d, 1H), 7.80 (s, 1H), 7.78 (s, 1H), 7.56 (d, J=7.8Hz, 1H), 7.37 (m, 1H), 7.29 (s, 2H), 5.30 (s, 2H), 3.81 (s, 3H).

Preparation 2551-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-imidazole-4-carboxylicacid methoxy-N-methyl-amide

Combine1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-imidazole-4-carboxylicacid methyl ester (0.46 g, 1.1 mmol) and N,O-dimethyl-hydroxylamine-HCl(0.16 g, 1.6 mmol) in THF (5.5 mL). Chill to 0° C., then slowly addisopropyl magnesium chloride (2M/THF, 1.6 mL, 3.2 mmol). After 45 min.,warm to RT. Add 70% sat. aq. NH₄Cl, and extract with EtOAc. Dry overMgSO₄, filter, and concentrate. Purify by flash chromatography on silicagel to give the title compound: MS (ES) 459.2 (M+1); ¹H NMR (300 MHz,CDCl₃) δ 8.63 (d, J=4.8 Hz, 1H), 8.52 (app d, 1H), 7.79 (s, 1H), 7.73(s, 1H), 7.63 (app d, J=8.1 Hz, 1H), 7.35–7.31 (m, 1H), 7.30 (s, 2H),5.21 (s, 2H), 3.79 (s, 3H), 3.37 (br s, 3H).

Preparation 2561-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-imidazol-4-yl]-3-(2-chloro-phenyl)-propynone

To a solution of 1-chloro-2-ethynylbenzene (0.11 mL, 0.92 mmol) inanhydrous THF (2.5 mL) add by syringe ethylmagnesium bromide, (0.26 mLof a 3.0 M soln. in ether, 0.78 mmol). After 30 min., add by syringe asolution of1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-imidazole-4-carboxylicacid methoxy-methyl-amide (0.30 g, 0.65 mmol) in THF (2.5 mL). After 1h., quench with sat. aq. NH₄Cl, and extract with EtOAc. Dry over MgSO₄,filter and concentrate under vacuum to give the title compound. MS (ES)534.1 (M+1); ¹H NMR (300 MHz, CDCl₃) δ 8.65 (s, 1H), 8.56 (s, 1H),7.86–7.21 (m, 10H), 5.23 (s, 2H).

Preparation 257[1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-imidazol-4-yl]-[5-(2-chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-4-yl]-methanone

To a solution of1-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-imidazol-4-yl]-3-(2-chloro-phenyl)-propynone(0.257 g, 0.48 mmol) in benzene (6 mL) add2-(2-nitroethoxy)tetrahydropyran (0.15 mL, 0.72 mmol), 1,4-phenylenediisocyanate (0.23 g, 1.44 mmol), and TEA (9 drops) with stirring.Attach a reflux condenser and set in a 100° C. oil bath. After 30 h.,remove from heat, add H₂O (5 mL), and stir 20 min. Filter the mixturethrough celite, wash with sat. aq. NaHCO₃, dry over MgSO₄, filter andconcentrate under vacuum. Purify the residue by flash chromatography,(EtOAc/Hexane 10%–85% then 7.5% MeOH/EtOA) to give the title compound.MS (ES) 691.2 (M+1); TLC R_(f) 0.25 (85% EtOAC/Hexane).

Preparation 258[1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-imidazol-4-yl]-[5-(2-chloro-phenyl)-3-[1,3]dioxolan-2-ylmethyl-isoxazol-4-yl]-methanone

Using a method similar to Preparation 257, the title compound may beprepared and isolated. MS (ES) 663.3 (M+1), TLC R_(f)=0.08 (85%EtOAC/Hexane).

Preparation 259[4-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-imidazole-4-carbonyl]-5-(2-chloro-phenyl)-isoxazol-3-yl]-acetaldehyde

Dissolve[1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-imidazol-4-yl]-[5-(2-chloro-phenyl)-3-[1,3]dioxolan-2-ylmethyl-isoxazol-4-yl]-methanone(0.23 g, 0.35 mmol) in acetic acid (4 mL) and add H₂O (2 mL). Attach areflux condenser and warm to 100° C. After 18 h., concentrate thesolution under reduced pressure, neutralize with sat. aq. NaHCO₃, andextract with CH₂Cl₂ and EtOAc (2×). Dry the combined organic layers overMgSO₄, filter, and concentrate to give the title compound: MS (ES) 619.2(M+1); TLC R_(f)=0.35 (5% MeOH/EtOAc).

Preparation 2601-(3,5-Bis-trifluoromethyl-benzyl)-S-phenyl-1H-imidazole-4-carboxylicacid methyl ester

Add 3,5-bis triflouromethyl benzyl amine (5.66 g, 23.30 mmol) to asolution (E/Z)-3-bromo-2-methyleneamino-3-phenyl-acrylic acid methylester (K. Nunami et al, J. Org. Chem. 1994, 59, 7635.) (5.20 g, 19.4mmol) and triethylamine (2.7 mL, 19.4 mmol) in DMF (60 mL). Stir thereaction mixture at RT for 16 h, then pour the mixture into saturatedaqueous NaHCO₃ and extract with CH₂Cl₂ (once) and EtOAc (three times).Dry the combined organic layers over MgSO₄, filter, and concentrate.Remove the excess DMF via azeoptropic distillation at reduced pressurewith xylenes. Purify the residue by flash chromatography (hexanes/EtOAcgradient) to yield 3.0 g (36%) of the title compound as a brown-orangesolid. ¹H NMR (300 MHz, CDCl₃) 7.83 (s, 2H) 7.79 (s, 1H), 7.75 (s 1H),7.35–7.5 (m, 3H), 7.25–7.49 (m, 2H), 5.15 (s, 2H), 3.77 (s, 3H); MS/ES429.1 (M+1).

Preparation 2611-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-imidazole-4-carboxylicacid

Add 5N NaOH (200 mL) to a solution of1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-imidazole-4-carboxylicacid methyl ester (3.0 g, 7.0 mmol) in EtOH (200 mL). Warm the mixtureto 70° C. and stir for 16 h. Then cool to RT and concentrate to 220 mLunder reduced pressure. Cool this solution to 0° C. and add conc. HCl topH 1. Filter the resulting precipitate and dry under vacuum to provide3.0 g (1100%) of the title compound as a light brown solid. ¹H NMR (300MHz, DMSO-d₆) δ 7.95 (s, 1H), 7.85 (s, 1R), 7.19–7.34 (m, SR), 7.15–7.02(m, 2R), 5.20 (s, 2R), 3.20 (br s, 11H); MS/ES 415.2 (M+1).

Preparation 2621-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-imidazole-4-carboxylicacid methoxy-N-methyl-amide

To a solution of1-(3,5-Bis-trifluoromethyl-benzyl)-S-phenyl-1H-imidazole-4-carboxylicacid (1.20 g, 2.90 mmol) in DMF (30 mL), add N-methoxy-N-methyl aminehydrochloride (424.1 mg, 4.35 mmol), EDCI (609.6 mg, 3.19 mmol), TEA(325.1 mg, 0.448 mL, 3.19 mmol), DMAP (11 mg, 0.087 mmol), and HOAT(433.6, 3.19 mmol). Stir the mixture at RT for 20 h., then pour into asolution of CH₂Cl₂ (100 ml) and brine (60 mL). Separate the layers andextract the aqueous layer with CH₂Cl₂ (5×) and EtOAc (2×). Dry thecombined organic layers over MgSO₄, filter and concentrate to providethe title compound that may be used without further purification. MS/ES458.0 (M+1), 456.0 (M−1).

Preparation 2631-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-imidazol-4-yl]-3-(2-chloro-phenyl)-propynone

Add ethyl magnesium bromide (1.26 ml of a 3 molar solution in THF, 3.77mmol) to a cooled (0° C.) soln. of 2-chlorophenyl acetylene (562 mg,4.12 mmol) in THF (35 mL). Stir for 1 h., then add1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-imidazole-4-carboxylicacid methoxy-methyl-amide (627 g, 1.371 mmol) as a solution in THF (10mL).

After 1 h., warm to RT and stir for another 8 h. Pour the mix into sat.NH₄Cl and extract with CH₂Cl₂ (2×), and EtOAc (2×). Dry over MgSO₄,filter, and concentrate. Purify by radial chromatography (hexanes/EtOAcgradient) to provide 560 mg of the title compound. ¹H NMR (300 MHz,CDCl₃) δ 7.85 (s, 1H), 7.82 (s, 1H), 7.45–7.15 (m, 11H), 5.21 (s, 2H).

Preparation 2641-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-3-trimethylsilanyl-2-yn-1-ol

Add n-butyl lithium (2.19 mL of a 1.6 molar solution in hex, 3.51 mmol)to a solution of trimethylsilylacetylene (444 mg, 639 uL, 4.52 mmol) inTHF (40 mL) at −78° C. After 25 min., add a solution of1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carbaldehyde(1.0 g, 2.51 mmol) in THF (6 mL) dropwise via cannula. After 1 h., warmthe mixture to RT. After 2 h, pour the mixture into sat. aq. NH₄Cl (15mL) and CH₂Cl₂ (15 mL). Separate the layers and extract the aqueouslayer with CH₂Cl₂ (3×15 mL) and with EtOAc (15 mL). Dry the combinedorganic layers over MgSO₄, filter, and concentrate. Purify the residueby chromatography on silica gel (hexanes/EtOAc gradient) to provide 245mg of the title compound as a yellow liquid. MS 497.14, ES/MS (M+1)498.3, ES/MS (M−1) 496.8. ¹H NMR (300 MHz, CDCl₃) δ 7.80–70 (m, 3H),7.60–7.18 (m, 5H), 5.51 (s, 2H), 5.35 (m, 1H), 0.02 (s, 9H).

Preparation 2651-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-3-trimethylsilanyl-propynone

To a solution of1-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-3-trimethylsilanyl-prop-2-yn-1-ol(20 mg, 0.040 mmol) in CH₂Cl₂ (2 mL) add oven dried 4 Å mol sieves (40mg), NaOAc (6.6 mg, 0.080 mmol), and pyridinium chlorochromate (13 mg,0.060 mmol). The mixture turns from orange to dark brown. After 2.5 h.,dilute the mixture with Et₂O (6 mL) and stir for 5 min, then pour themixture through a plug of Celite (1 cm) and silica gel (2 cm).Concentrate the filtrate and purify the residue by chromatography onsilica gel (hexanes/EtOAc gradient) to provide 6 mg of the titlecompound as a faintly yellow liquid. R_(f)=0.6 (50:50 EtOAc/hexanes).

Preparation 266[1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-(3-phenyl-5-trimethylsilanyl-3H-[1,2,3]triazol-4-yl)-methanone

In a pressure vessel add phenyl azide (0.029 g, 0.23 mmol) with stirringto a solution of1-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-3-trimethylsilanyl-propynone(0.058 g, 0.12 mmol) in toluene (1 mL). Seal the vessel and set in a120° C. oil bath. After 24 h., remove from heat, concentrate, and purifyby flash chromatography, (EtOAc/Hexane 0%–50%) to give the titlecompound. MS(ES) 615.2 (M+1), TLC R_(f)=0.24 (30% EtOAc/Hexane).

EXAMPLES General Example A

Dissolve the alkyne of interest (1 eq.) in benzene (0.1 M). Add theappropriate nitro compound (1.5 eq.), 1,4-phenylene diisocyanate (3eq.), and TEA (10 drops/mmol alkyne). Attach a reflux condenser andplace in 110° C. bath, and stir. After 20 h., add additional nitrocompound (0.5 eq.), 1,4-phenylene diisocyanate (1 eq.) and TEA. After anadditional 6 h., remove from heat, add H₂O, and stir 20 min. Filterthrough Celite®, remove H₂O, and dry over MgSO₄. Filter and concentrateunder vacuum. Purify by chromatography on silica gel.

By the method of General Example A, the following compounds may beprepared.

Ex. # R⁷ R^(b) Physical Data 1 methyl 2-chloro MS (ES) 591.1 (M+1), ¹HNMR (300 MHz, CDCl₃): δ 7.84 (s, 1H), 7.74 (d, J = 2.5 Hz, 1H), 7.70 (d,J = 2.2 Hz, 1H), 7.56–7.19 (m, 9H), 5.44 (s, 2H), 2.51 (s, 3H). 2 ethyl2-chloro MS (ES) 605.1 (M+1), ¹H NMR (300 MHz, CDCl₃): δ 7.66 (s, 1H),7.54 (dd, J = 7.8, 3.0 Hz, 1H), 7.45–7.00 (m, 10H), 5.26 (s, 2H), 2.77(q, J = 6.5 Hz, 2H), 1.16 (t, J = 6.5 Hz, 3H). 3 propyl 2-chloro MS (ES)619.1 (M+1), ¹H NMR (300 MHz, CDCl₃): δ 7.73 (s, 1H), 7.60 (dd, J = 6.5,1.0 Hz, 1H), 7.48–7.05 (m, 10H), 5.32 (s, 2H), 2.80 (appt, J = 7.0 Hz,2H), 1.68 (app t. J = 7.0 Hz, 2H), 0.90 (t, J = 6.5 Hz, 3H). 4 methylhydrogen MS (ES) 557.3 (M+1), TLC (30% EtOAc/Hexane), R_(f) = 0.26 5methyl 4-fluoro MS (ES) 575.3 (M+1), TLC (30% EtOAc/Hexane), R_(f) =0.28 6 methyl 3-trifluoro- MS (ES) 625.0 (M+1), TLC (50% EtOAc/Hexane×2), R_(f) = methyl 0.38 7 methyl 2-fluoro MS (ES) 575.0 (M+1), ¹H NMR(300 MHz, CDCl₃): δ 7.77–7.11 (m, 12H), 5.40 (s, 2H), 2.37 (s, 3H). 8methoxy- 2-chloro Exact Mass 634.1: MS (aspci): m/z = 635.1 (M+1), 633.1carbonyl (M−1); ¹H NMR (250 MHz, CDCl₃) δ 7.74 (s, 1H), 7.56- 7.08 (m,11H), 5.50 (5, 2H), 3.85 (s, 3H). 9 methoxy- 2-chloro Exact Mass 620.1:MS (aspci): m/z = 622.9 (M+1); ¹H methyl NMR (300 MHz, CDCl₃) δ 7.74 (s,2H), 7.60 (m, 1H), 7.49– 7.35 (m, 3H), 7.34 (m, 1H), 7.27 (s, 2H),7.23–7.10 (m, 3H), 5.39 (s, 2H), 4.67 (s, 2H), 3.26 (s, 3H).

By the method of General Example A, the following compounds may beprepared.

Ex. # R⁵ R⁷ Physical Data 10 pyridin-4-yl methyl Exact Mass 591.09: MS(ESI) m/z 592.2 (M+1). ¹H NMR (300 MHz, CDCl₃) δ2.49 (s, 3H), 5.43 (s,2H), 7.18 (m, 3H), 7.24–7.48 (m, 4H), 7.72 (dd, 1H, J = 7.61, 1.56 Hz),7.86 (s, 1H), 8.80 (m, 2H). 11 pyridin-3-yl methyl Exact Mass;/591.09;MS (ESI) m/z 592.2 (M+1). ¹H NMR (300 MHz, CDCl₃) δ 2.49 (s, 3H), 5.47(s, 2H), 7.20–7.45 (m, 6H), 7.61 (m, 1H), 7.72 (dd, 1H, J = 7.52, 1.77Hz), 7.84 (s, 1H), 8.51 (s, 1H), 8.78 (m, 1H). 12 pyrimidin-5- methyl ¹HNMR (400 MHz, CDCl₃) δ2.50 (s, 3H), 5.49 (s, yl 2H), 7.22 (d, J = 8.4Hz, 1H), 7.35–7.39 (m, 3H), 7.44 (t, J = 7.6 Hz, 1H), 7.75 (d, J = 7.6Hz, 1H), 7.88 (s, 1H), 8.66 (s, 2H), 9.36 (s, 1H); MS (apci) m/z 593.1(M+1) 13 methyl methyl MS (ES) 529.1 (M+H), 527.1 (M—H). ¹H NMR (400MHz, CHCl₃) δ 7.89 (s, 1H), 7.67 (dd, 1H, J = 7.9, 2.0 Hz), 7.54 (s,2H), 7.37 (dt, 1H, J = 7.6, 1.5 Hz), 7.31 (dt, 1H, J = 7.6, 2.0 Hz),7.20 (dd, 1H, J = 7.9, 1.5 Hz), 5.52 (s, 2H), 2.53 (s, 3H), 2.52 (s,3H). 14 chloro methyl MS (ES+) 549.0 (M+1). ¹H NMR (400 MHz, CDCl₃) δ7.89 (s, 1H), 7.65 (s, 2H), 7.62 (dd, 1H, J = 1.5, 7.8 Hz), 7.32 (dt,1H, J = 1.4, 7.4 Hz), 7.26 (dt, 1H, J = 1.4, 7.8 Hz), 7.11 (dd, 1H, J =1.0, 7.8 Hz), 5.53 (s, 2H), 2.52 (s, 3H). 15 pyridin-3-yl cyclo- MS(ES+) 618.2 (M+H). ¹H NMR (400 MHz, CDCl₃) δ propyl 8.78 (br s, 1H),8.52 (br s, 1H), 7.82 (s, 1H), 7.70 (dd, 1H, J = 7.8, 1.8), 7.62 (m,1H), 7.41 (m, 2H), 7.33 (m, 3H), 7.20 (dd, 1H, J = 7.8, 10), 5.47 (s,2H), 2.25 (m, 1H), 1.14(m, 2H), 1.03(m, 2H).

By the method of General Example A, the following compounds may beprepared.

Ex. # R^(a) R⁵ Physical Data 16 3,5-dichloro pyridin-4- MS (ES) 524.3,526.3 (M⁺+1). yl 17 2-methoxy-5- pyridin-3- MS (ES+) 570.1 (M+1)⁺.trifluoromethoxy yl ¹H NMR (400 MHz, CDCl₃) δ 8.71 (m, 1H), 8.46 (m,1H), 7.68 (m, 2H), 7.36 (m, 3H), 7.24 (m, 1H), 7.12 (m, 1H), 6.75 (m,1H), 6.50 (s, 1H), 5.34 (s, 2H), 3.61(s, 3H), 2.47(s, 3H).

Example 18[1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-imidazol-4-yl]-[5-(2-chloro-phenyl)-3-methyl-isoxazol-4-yl]-methanone

Using the method of General Example A, and the appropriate startingmaterials, the title compound may be prepared and isolated. Exact Mass589.1; MS (aspci) m/z=589.9 (M+1), m/z=588.0 (M−1); ¹H NMR (300 MHz,CDCl₃) δ 7.79 (s, 1H), 7.60 (m, 1H), 7.50–7.35 (m, 3H), 7.35–7.18 (m,6), 7.18 (s, 2H), 5.05 (s, 2H), 2.45 (s, 3H).

General Example B

Dissolve the appropriate alkyne (1 eq.) in toluene (0.1 M) and treat thesolution with the appropriate nitroalkoxy-tetrahydropyran (5 eq.),1,4-diisocyanato-benzene (5 eq.), and triethylamine (5 eq.). Heat thesolution at 110° C. overnight, then add water and filter through a padof Celite®. Wash the solid with EtOAc and wash the filtrate with brine.Dry over MgSO₄, filter, and concentrate to give the crude isoxazole.

Dissolve the residue in MeOH (0.1M) and treat with AcOH or p-TsOH.H₂O(2eq.). Stir the solution at RT for 18 h. Concentrate the solution andre-dissolve the crude material in EtOAc. Wash the organic solution withsaturated NaHCO₃, then dry, filter, and concentrate. Purify the crudematerial by flash chromatography to give the title compound.

By the method of General Example B, the following compounds may beprepared and isolated.

Ex. # R⁵ R⁷ Physical Data 19 chloro hydroxy- MS (ES) 565.0 (M+1). ¹H NMR(400 MHz, CDCl₃) δ methyl 7.91 (s, 1H), 7.65 (s, 2H), 7.63 (dd, 1H, J =1.8, 8.0 Hz), 7.36 (dt, 1H, J = 1.5, 7.3 Hz), 7.31 (dt, 1H, J = 1.9, 7.8Hz), 7.11 (dd, 1H, J = 1.5, 7.8 Hz), 5.55 (s, 2H), 4.84 (d, 2H, J = 7.4Hz), 3.74 (t, 1H, J = 7.4 Hz). 20 chloro 2- MS (ES) 579.0 (M+1); ¹H NMR(400 MHz, CDCl₃) δ hydroxy- 7.90 (s, 1H), 7.64 (s, 2H), 7.63 (m, 1H),7.33 (dt, 1H, J = ethyl 1.0, 7.3 Hz), 7.27 (dt, 1H, J = 1.5, 7.8 Hz),7.12 (dd, 1H, J = 1.0, 7.8 Hz), 5.53 (s, 2H), 4.05 (t, 2H, J = 5.9 Hz),3.19 (t, 2H, J = 5.9 Hz), 2.35 (br s, 1H). 21 methyl hydroxy- MS (ES)545.1 (M+H), 543.1 (M—H). ¹H NMR (400 methyl MHz, CDCl₃) δ 7.90 (s, 1H),7.69 (dd, 1H, J = 7.6, 2.2 Hz), 7.55 (s, 2H), 7.35–7.40 (m, 2H), 7.22(dd, 1H, J = 8.0, 1.6 Hz), 5.53 (s, 2H), 4.85 (d, 2H, J = 7.6 Hz), 4.08(t, 1H, J = 7.6 Hz , 2.55 (s, 3H). 22 methyl 2- MS (ES) 558.9 (M⁺), MS(ES−) 556.9 (M−1)⁻. ¹H NMR hydroxy- (400 MHz, CDCl₃) δ 7.87 (s, 1H),7.67 (dd, 1H, J = 2.0, ethyl 7.3 Hz), 7.51 (s, 2H), 7.36 (dt, 1H, J =1.5, 7.3 Hz), 7.30 (dt, 1H, J = 2.0, 7.8 Hz), 7.18 (dd, 1H, J = 1.5, 7.8Hz), 5.49 (s, 2H), 4.05 (t, 2H, J = 5.4 Hz), 3.17 (t, 2H, J = 5.4 Hz),2.51 (s, 3H), 1.70 (br s, 1H). 23 pyrimidin- hydroxy- ¹H NMR (400 MHz,CDCl₃) δ 3.59 (t, J = 7.2 Hz, 1H), 5-yl methyl 4.82 (d, J = 6 Hz, 2H),5.52 (s, 2H), 7.26 (d, J = 0.8 Hz, 1H), 7.35–7.40 (m, 3H), 7.42 (t, J =6 Hz, 1H), 7.76 (d, J = 4 Hz, 1H), 7.89 (s, 1H), 8.66 (s, 2H), 9.38 (s,1H); MS (apci) m/z 609.0 (M+1) 24 pyridin-3- 2- ¹H NMR (300 MHz, CDCl₃)δ 3.15 (t, J = 5.93 Hz, 2H), yl hydroxy- 4.02 (t, J = 5.86 Hz, 2H), 5.47(s, 2H), 7.21–7.45 (m, 6H), ethyl 7.61 (m, 1H), 7.72 (dd, J = 7.59, 1.87Hz, 1H), 7.84 (s, 1H), 8.51 (d, J = 1.63 Hz, 1H), 8.78 (m, 1H); MS(ESI)m/z 604.1 (M—OH). 25 pyrimidin- 2- ¹H NMR (400 MHz, CDCl₃) δ 2.34 (t, J= 6.4 Hz, 1H), 5-yl hydroxy- 3.16 (t, J = 5.6 Hz, 2H), 4.03 (q, J = 5.6Hz, 2H), 5.49 (s, ethyl 2H), 7.23 (d, J = 8 Hz, 1H), 7.36–7.40 (m, 3H),7.45 (t, J = 7.6 Hz, 1H), 7.76 (d, J = 8 Hz, 1H), 7.88 (s, 1H), 8.66 (s,2H), 9.36 (s, 1H); MS (apci) m/z 623.0 (M+1).

Example 26[5-(2-chloro-phenyl)-3-hydroxymethyl-isoxazol-4-yl]-[1-(2-methoxy-5-trifluoromethoxy-benzyl-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-methanone

Using the method of General Example B, the title compound may beprepared. MS (ES+) 586.1 (M+1)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.72 (m, 1H),8.48 (m, 1H), 7.68 (m, 2H), 7.40 (m, 3H), 7.26 (m, 1H), 7.15 (m, 1H),6.76 (d, 1H, J=8.8 Hz), 6.55 (m, 1H), 5.35 (s, 2H), 4.80 (d, 2H, J=6.8Hz), 3.90 (t, 1H, J=6.8 Hz), 3.63 (s, 3H).

Example 27[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-[5-(2chloro-phenyl)-3-(1-hydroxy-1-methyl-ethyl)-isoxazol-4-yl]-methanone

Combine1-[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-3-(2-chloro-phenyl)-propynone(0.31 g, 0.58 mmol), 1,4-phenylene diisocyanate (0.48 g, 3.0 mmol),(1,1-dimethyl-2-nitro-ethoxy)-trimethyl-silane (3.0 g, 1.5 mmol),triethylamine (8 drops) and benzene (10 mL), stir, and heat at reflux.After 18 h., cool to ambient temperature, filter the brown precipitate,wash with ethyl acetate, and concentrate. Purify the resulting mixtureby silica gel chromatography eluting with 1:1 EtOAc/hexanes to give[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-{5-(2-chloro-phenyl)-(1-methyl-1-trimethylsilanyloxy-ethyl)-isoxazol-4-yl}-methanone(0.20 g, 0.28 mmole).

Dissolve the residue in THF (5 mL) and add TBAF (0.31 mL of a 1M soln.,0.31 mmole). Stir for 30 min., then evaporate the solvent and purify theproduct by flash chromatography, eluting with 2:1 EtOAc/hexane to givethe title compound (35 mg, 23%). ¹H NMR (300 MHz, CDCl₃) δ 1.55 (s, 6H),5.40 (s, 2H), 7.15 (d, J=7.81 Hz, 1H), 7.19 (m, 2H), 7.31 (t, J=7.81 Hz,1H), 7.36 (s, 2H), 7.41 (t, J=7.66, Hz, 1H), 7.70 (m, 1H), 7.87 (s, 1H),8.82 (m, 2H); MS (ESI) m/z 636.0(M+1).

By a method similar to Example 27, with the appropriate startingmaterials, the following compounds are prepared and isolated.

Ex. # R⁵ Physical Data 28 pyridin-3-yl Exact Mass 635: MS (aspci): m/z =618.17 (M—H₂O); ¹H NMR (300 MHz, CDCl₃) δ 8.68 (d, J = 3.3 Hz, 1H), 8.51(d, J = 0.9 Hz, 1H), 8.05 (s, 1H), 7.82 (d, J = 2.7 Hz, 1H), 7.38–7.59(m, 7H), 5.82 (s, 2H), 1.54 s, 6H. 29 pyrimidin-5- ¹H NMR (400 MHz,CDCl₃) δ 1.66 (s, 6H), 4.78 (s, 1H), 5.46 (s, 2H), yl 7.19 (d, J = 8 Hz,1H), 7.37–7.42 (m, 3H), 7.44 (t, J = 7.6 Hz, 1H), 7.74 (d, J = 7.6 Hz,1H), 7.89 (s, 1H), 8.67 (s, 2H), 9.39 (s, 1H); MS (apci) m/z 619.1(M+1-H₂O).

General Example C

Add triethylamine (2.5 eq.) to a solution of 2-chlorophenylhydroximimoylacid chloride (2.0 eq.) and the appropriate alkyne (1.0 eq.) in EtOAc.Stir the mixture at RT to 50° C. until the reaction is complete. Treatthe reaction mixture with saturated sodium bicarbonate solution, extractwith ether (3×50 mL). Dry the combined organic layers with MgSO₄,filter, and concentrate in vacuo. Purify by chromatography on silicagel.

By the method of General Example C, the following compounds may beprepared and isolated.

Ex. # R⁵ R⁷ Physical Data 30 pyridin-4-yl Hydrogen MS (ES) 578.1 (M⁺+1);TLC (50% EtOAc in hexanes): R_(f) = 0.3. 31 pyridin-3-yl Hydrogen MS(ES) 578.1 (M⁺+1); TLC (50% acetone in hexanes): R_(f) = 0.3. 32pyridin-4-yl methoxy- m.p. 128° C. (decomp.) TLC: R_(f) = 0.16 (1:1methyl hexanes/EtOAc) MS(ES) 621.9 (M⁺) 33 chloro methoxy- TLC: R_(f) =0.38 (2:1 hexanes/EtOAc) MS(ES) 578.9 methyl (M⁺)

General Example D

Dissolve the appropriate tetrahydropyranyl-protected alcohol (1 eq.) inTHF, water and HOAc and heat at 60° C. Stir 5–24 h., concentrate invacuo, extract with EtOAc, wash with water, saturated aqueous NaHCO₃,brine, dry (Na₂SO₄), filter and concentrate in vacuo. Purify bychromatography to give the title compound.

Using the method of General Example D, the following compounds may beprepared and isolated.

Ex. # R⁵ R⁷ Physical Data 34 pyrazin-2-yl hydoxy- MS(ES) 609.1 (M+1);TLC R_(f) = 0.50(20% methyl CH₃CN/CH₂Cl₂) 35 phenyl hydroxy- MS (ES)607.0 (M+1); ¹H NMR (300 MHz, CDCl₃): δ methyl 7.85 (s, 1H), 7.74 (d, J= 7.4 Hz, 1H), 7.62–7.37 (m, 5H), 7.35 (s, 2H), 7.27–7.20 (m, 3H), 5.45(s, 2H), 4.83 (d, J = 7.2 Hz, 2H), 3.85 (t, J = 7.2 Hz, 1H). 36 phenyl2- MS (ES) 620.1 (M⁺); ¹H NMR (300 MHz, CDCl₃): δ hydroxy- 7.74 (s, 1H),7.63 (dd, J = 7.5, 1.9 Hz, 1H), 7.50–7.09 ethyl (m, 10H), 5.34 (s, 2H),3.94 (t, J = 6.0 Hz, 2H), 3.08 (t, J = 6.0 Hz, 2H. 37 pyrimidin-5-hydroxy- Exact Mass 608.08; MS (apci): m/z = 609.0 (M+1); ¹H yl methylNMR (400 MHz, CDCl₃): δ 9.38 (s, 1H), 8.67 (s, 2H), 7.89 (s, 1H), 7.76(d, J = 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H),7.42 (s, 2H), 7.24 (d, J = 8 Hz, 1H), 5.51 (s, 2H), 4.82 (d, J = 7.2 Hz,2H), 3.58 (t, J = 7.2 Hz, 1H). 38 pyridin-3-yl hydroxy- MS(APCI) m/z608(M+1); ¹H NMR (300 MHz, CDCl₃) δ methyl 4.81 (d, J = 7.26 Hz, 2H),5.48 (s, 2H), 7.23 (d, J = 7.82 Hz, 1H), 7.34–7.46 (m, 5H), 7.58–7.61(m, 1H), 7.73 (dd, J = 7.65, 1.72 Hz, 1H), 7.85 (s, 1H), 8.52 (d, J =1.84 Hz, 1H), 8.80(m, 1H). 39 pyridin-4-yl hydroxy- MS(ESI) m/z608.1(M+1); ¹H NMR (300 MHz, CDCl₃) δ methyl 3.64 (br s, 1H), 4.81(s,2H), 5.45 (s, 2H), 7.14–7.22 (m, H), 7.38–7.47 (m, 4H), 7.74 (dd, J =7.61, 1.76 Hz, 1H), 7.87 (s, 1H), 8.82 (br s, 2H). 40 hydrogen hydroxy-¹H NMR (300 MHz, CDCl₃) δ 4.84 (s, 2H), 5.61 (s, 2H), methyl 7.22–7.25(m, 1H), 7.33–7.39 (m, 2H), 7.63 (s, 2H), 7.93 (s, 1H), 8.11 (s, 1H); MS(APCI) m/z 530.9 (M+1). 41 pyridin-4-yl 2- ¹H NMR (300 MHz, CDCl₃) δ2.50 (br s, 1H), 3.15 (t, J = hydroxy- 5.87 Hz, 2H), 4.02 (t, J = 6.05Hz, 2H), 5.45 (s, 2H), ethyl 7.16–7.22 (m, 3H), 7.32–7.38 (m, 3H), 7.42(td, J = 7.61, 1.17 Hz, 1H), 7.73 (dd, J = 7.71, 1.66 Hz, 1H), 7.86 (s,1H), 8.79 (m, 2H); MS (ESI) m/z 622.3 (M+1). 42 hydrogen 2- ¹H NMR (300MHz, CDCl₃) δ 1.62 (bs, 1H), 3.19–3.23 hydroxy- (m, 2H), 4.05–4.09 (m,2H), 5.59 (s, 2H), 7.21–7.37 (m, ethyl 3H), 7.63–7.65 (m, 3H), 7.93 (s,1H), 8.07 (m, 1H); MS (APCI) m/z 527.1 (M−17).

Example 43[1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-[4-(2-chloro-phenyl)-3-hydroxymethyl-isoxazol-5-yl]-methanone

By the method of General Example D, the title compound is prepared andisolated. ¹H NMR (500 MHz, DMSO-d₆): δ 8.67 (dd, 1H, J=1.5, 5.0), 8.59(d, 1H, J=2.0), 8.07 (s, 1H), 7.88 (dt, 1H, J=1.9, 8.0), 7.72 (s, 2H),7.50 (m, 2H), 7.44 (m, 1H), 7.36 (m, 2H), 5.84 (m, 2H), 5.50 (br t, 1H,J=5.8), 4.49 (br s, 2H).

By the method of General Example D, the following compounds may beprepared and isolated.

Ex. # R^(a) R⁵ Physical Data 44 3,5-dichloro pyridin-4-yl MS (ES) 540.2(M⁺+1) 45 3,5-dichloro pyridin-3-yl MS (ES) 539.9, 541.9 (M⁺+1), R_(f) =0.355 (6.7% MeOH/CH₂Cl₂) 46 3-trifluoro- pyridin-3-yl MS (ES) 540.1,542.1 (M⁺+1), R_(f) = 0.15 (6.7% methyl MeOH/CH₂Cl₂) 47 4-trifluoro-pyridin-3-yl MS (ES) 540.1, 542.2 (M⁺+1), R_(f) = 0.11(6.7% methylMeOH/CH₂Cl₂) 48 2,5-bis- pyridin-3-yl MS (ES) 608.1, 610.2 (M⁺+1), R_(f)= 0.37 (50% trifluoro- EtOAc/CH₂Cl₂) methyl

By the method of General Example D, the following compounds may beprepared and isolated.

Ex. # R^(a) R⁵ Physical Data 49 3,5-dichloro pyridin-3- R_(f) = 0.15(2:1 Hex/EtOAc); MS (ES) 540.0 (M+1) yl 50 3-trifluoro- pyridin-3- R_(f)= 0.14 (1:2 Hex/EtOAc); MS (ES) 556.0 (M+1) methoxy yl 51 3,5-dimethylpyridin-3- MS (ES) 500.1 (M+1) yl 52 2-fluoro-5- pyridin-3- R_(f) = 0.221:2 Hex/EtOAc; MS (ES) 558.0 (M+1) trifluro- yl methyl 53 2-methoxy-5-pyridin-3- R_(f) = 0.13 1:2 Hex/EtOAc; MS (ES) 586.0 (M+1) trifluoro- ylmethoxy

Example 54[1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-imidazol-4-yl]-[5-(2-chloro-phenyl)-3-hydroxymethyl-isoxazol-4-yl]-methanone

Using the method of General Example D, the title compound may beprepared and isolated. Exact Mass 605.09; mass spectrum (aspci):m/z=605.9(M+1), m/z=603.9(M−1); ¹H NMR (300 MHz, CDCl₃) δ 7.73 (s, 2H),7.52 (m, 1H), 7.45–7.05 (m, 10H), 4.98 (s, 2H), 4.67 (s, 2H).

Example 55[1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-imidazol-4-yl]-[5-(2-chloro-phenyl)-3-hydroxymethyl-isoxazol-4-yl]-methanone

Dissolve[1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-imidazol-4-yl]-[5-(2-chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-4-yl]-methanone(0.136 g, 0.20 mmol) in THF (1.5 mL), add acetic acid (1.5 mL) and H₂O(0.5 mL). Attach a reflux condenser and stir 20 hours in a 60° C. oilbath. Concentrate under vacuum, neutralize with saturated aqueousNaHCO₃, and extract with EtOAc. Dry over MgSO₄, filter through paper,and concentrate under vacuum. Recrystallize in ether/hexane (1:10) togive the title compound: MS (ES) 607.1 (M+1), ¹H NMR (CDCl₃) δ 8.69 (brs, 1H), 8.58 (br s, 1H), 7.82 (s, 1H), 7.64 (m, 2H), 7.44–7.28 (m, 5H),7.23 (s, 2H), 5.14 (s, 2H), 4.76 (s, 2H).

General Example E

Combine the appropriate protected alcohol (1.0 eq.) in MeOH, addp-toluenesulfonic acid (1.3 eq.) and allow the mixture to stir at RT.After 18 h., concentrate the solution in vacuo, dilute the residue inether, and wash the solution with aqueous saturated sodium bicarbonatesolution. Dry over MgSO₄, filter, and concentrate in vacuo. Purify theresidue by flash chromatography on silica gel to give the titlecompound.

By the method of General Example E, the following compounds are preparedand isolated.

Ex. # R⁵ R⁷ Physical Data 56 chloro hydroxy- MS (ES) 564.9 (M+1); TLCR_(f) = 0.1 (30% hexanes in methyl Et₂O). 57 phenyl hydroxy- MS (ES)607.0 (M+1); TLC R_(f) = 0.1(20% ether in methyl hexanes). 58 4-methyl-2-hydroxy- MS (ES) 643.0 (M⁺+1); TLC R_(f) = 0.1 (2.5% MeOH inpiperazin-1- ethyl dichloromethane). yl 59 thio- 2-hydroxy- MS (ES)645.9 (M⁺+1); TLC R_(f) = 0.1, (50% EtOAc in morphlino ethyl hexanes).60 dimethyl- 2-hydroxy- MS (ES) 587.9 (M⁺+1); TLC R_(f) = 0.1 (50% EtOAcin amino ethyl hexanes). 61 morpholino 2-hydroxy- MS (ES) 629.9 (M⁺+1);TLC R_(f) = 0.1 (50% EtOAc in ethyl hexanes). 62 pyridin-4-yl 2-hydroxy-MS (ES) 621.9 (M⁺+1); TLC R_(f) = 0.5 (50% EtOAc in ethyl hexanes). 63pyridin-4-yl hydroxy- MS (ES) 608.0 (M⁺+1); TLC R_(f) = 0.1 (50% EtOAcin methyl hexanes). 64 pyridin-3-yl hydroxy- MS (ES) 607.9 (M⁺+1); TLCR_(f) = 0.1(50% EtOAc in methyl hexanes). 65 chloro 1-hydroxy-1- m.p.116° C. TLC: R_(f) = 0.35 (2:1 hexanes/EtOAc) methyl-ethyl MS(ES) 592.8(M+1), 574.8 [(M—OH)⁺]

By the method of General Example E, the following compounds are preparedand isolated.

Ex. # R⁶ Physical Data 66 3-chloro-pyridin-4- MS (ES) 617.0, 619.0(M⁺+1). R_(f) = 0.27 (6.25% yl MeOH/CH₂Cl₂) 67 4-chloro-pyridin-3- R_(f)= 0.30 (6.67% MeOH/CH₂Cl₂) yl 68 2-chloro-pyridin-3- MS (ES) 617.0,619.0 (M⁺+1). R_(f) = 0.29 (6.25% yl MeOH/CH₂Cl₂) 69 2,6-difluoro-phenylMS (ES) 617.9 (M⁺+1); R_(f) = 0.40 (10:1 CHCl₃/MeOH) 702,6-dichloro-phenyl MS (ES) 649.9 (M⁺+1); R_(f) = 0.43 (10:1 CHCl₃/MeOH)

Example 71[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyrazin-2-yl-1H-[1,2,3]triazol-4-yl]-[3-(2-chloro-5-hydroxymethyl-isoxazol-4-yl]-methanone

Dissolve[1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyrazin-2-yl-1H-[1,2,3]triazol-4-yl]-[5-(tert-butyl-dimethyl-silanyloxymethyl)-3-(2-chloro-phenyl)-isoxazol-4-yl]-methanone(0.45 g, 1 eq.) in THF and add tetrabutylammonium flouride solution(0.74 mL 1.2 eq., 1N in THF). Stir 1.5 h. at RT, then dilute with EtOAcand wash with saturated aqueous NaHCO₃ and brine. Dry over Na₂SO₄,filter and concentrate in vacuo. Purify the residue by chromatography onsilica gel. MS (ES) 609.1 (M+1)⁺; TLC R_(f)=0.43 (10% MeOH/CHCl₃).

By the method of Example 71, using the appropriate silylether, thefollowing compounds may be prepared.

Ex. # R⁵ Physical Data 72 pyrazin-2-yl MS (ES) 637.2 (M+1)⁺; TLC R_(f) =0.50 10% MeOH/CHCl₃) 73 morpholino m.p. 188° C.; TLC: R_(f) = 0.38 (1:1hexanes/EtOAc); MS(ES) 643.9 (M+1), 625.9 (M−OH)

Example 74[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-[3-(3-chloro-pyridin-4-yl)-5-(1-hydroxy-1-methyl-ethyl)-isoxazol-4-yl]-methanone

Using the method of Example 71, with the appropriate silylether, thetitle compound may be prepared and isolated. MS (ES) 637.0 (M⁺+1);R_(f)=0.29 (6.67% MeOH/CH₂Cl₂).

By a method similar to Example 71, the following compounds may beprepared and isolated.

Ex. # R⁵ Physical Data 75 pyrazin-2-yl R_(f) = 0.53 (1:2 Hex/EtOAc); MS(ES) 637.3 (M+1) 76 morpholino R_(f) = 0.12 (2:1 Hex/EtOAc); MS (ES)644.1 (M+1). 77 phenyl MS (ES) 635.1 (M+1); R_(f) = 0.32 (2:1 Hex/EtOAc)

Example 78[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-[3-(2-chloro-phenyl)-5-(1-hydroxy-1-methyl-ethyl)-isoxazol-4-yl]-methanone

Dissolve 2-chloro-N-hydroxybenzenecarboximidoyl chloride (380 mg, 2.0mmol, 2 eq.) and1-[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-4-methyl-4-trimethylsilanyloxy-pent-2-yn-1-one(555 mg, 1.0 mmol) in EtOAc (2.5 mL). Add TEA (348 μL, 252 mg, 2.5 eq.)dropwise and stir at RT. After 18 h., dilute with EtOAc (10 mL). Washwith saturated NaHCO₃ (10 mL), and brine (5 mL), then dry (MgSO₄),filter, and concentrate.

Dissolve the crude residue in THF (5 mL) and cool to 0° C. Add TBAF(Aldrich, 1.2 mL of a 1M soln in THF, 1.2 mmol, 1.2 eq.). After 2 h.,dilute with EtOAc (20 mL). Wash with water (10 mL) and brine (10 mL).Dry (MgSO₄), filter, and concentrate. Purify by chromatography (silicagel, hexanes/EtOAc 1:1 to 1:2 gradient) to give the title compound as ayellow solid. Recrystallize from hexanes/EtOAc to give 173 mg (26%) ofthe title compound as a white solid. TLC: R_(f)=0.2 (1:2 hexanes/EtOAc);MS(ES): 636.0 (M+1).

Example 79[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-[3-(2-chloro-phenyl)-5-(1-hydroxy-1-methyl-ethyl)-isoxazol-4-yl]-methanone

Using the method of Example 78, the title compound may be prepared andisolated. m.p.=105° C.; TLC: R_(f)=0.86 (1:2 hexanes/EtOAc); MS(ES)618.2 [M−OH]⁺.

Example 80[1-(3,5-bis-trifluoromethyl-benzyl)-5-imidazol-1-yl-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl-3-(1-hydroxy-1-methyl-ethyl)-isoxazol-4-yl]-methanone

To a solution of[1-(3,5-Bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-3-(1-methyl-1-trimethylsilanyloxy-ethyl)-isoxazol-4-yl]-methanone(40 mg, 0.06 mmol) in DMSO (0.5 mL), add imidazole (41 mg, 0.60 mmol)and heat to 80° C. for 12 h. Cool to RT and dilute with EtOAc (3 mL).Wash the solution with 1N HCl (3 ml) and H₂O (3 mL). Pass organic layerthrough Varian ChemElute® drying cartridge and concentrate.Chromatograph crude material using a gradient (10:1 to 1:5 Hex/EtOAc) toafford the title compound (18.2 mg, 49%). R_(f)=0.53 (1:5 Hex/EtOAc);MS/ES 625.1 (M+1).

Example 81[1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazol-4-yl]-[3-(2-chloro-phenyl)-5-(1-hydroxy-ethyl)-isoxazol-4-yl]-methanone

Dissolve1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazo-4-yl]-[5-(1-tert-butoxy-ethyl)-3-(2-chloro-phenyl)-isoxazol-4-yl]-methanone(160 mg, 0.23 mmol) in TFA (1 mL) and stir at RT overnight. Dilute withEtOAc (10 mL) and wash with 1N NaOH (3×5 mL), saturated NaHCO₃ (5 mL),and brine (5 mL). Dry (MgSO₄), filter, and concentrate. Purify theresidue by chromatography (silica gel, hexanes/EtOAc 2:1 to 1:1gradient) to give 126 mg of a white solid. Recrystallize fromhexanes/EtOAc to provide 92 mg (63%) of the title compound. m.p.145–146° C.; TLC: R_(f)=0.28 (1:1 hexanes/EtOAc); MS(ES) 629.9 (M+1).

General Example F

Dissolve the appropriate 5-chlorotriazole (1 eq.) in the appropriateamine (20–120 eq.) and stir at 80–110° C. The amine may be in solutionin a suitable solvent, such as MeOH, DMSO, or THF. After 2–20 h., dilutethe solution with EtOAc (25 mL) and wash with 1N HCl (20 mL), water (20mL), and saturated NaHCO₃ (20 mL). Dry, filter, and concentrate theorganic phase then purify the residue by flash chromatography on silicagel.

Using the above method, with the appropriate starting materials, thefollowing compounds may be prepared and isolated.

Ex. # R⁵ R⁷ Physical Data 82 morpholino hydroxy- MS (ES) 616.1 (M+1), MS(ES−) 614.1 (M−1); ¹H methyl NMR (400 MHz, CDCl₃) δ 7.87 (s, 1H), 7.67(dd, 1H, J = 1.5, 7.8 Hz), 7.62 (s, 2H), 7.37 (dt, 1H, J = 1.4, 7.4 Hz),7.29 (dt, 1H, J = 1.4, 7.8 Hz), 7.12 (dd, 1H, J = 1.0, 7.8 Hz), 5.43 (s,2H), 4.82 (d, 2H, J = 6.8 Hz), 4.03 (t, 1H, J = 7.6 Hz), 3.74 (m, 4H),3.00 (m, 4H). 83 morpholino 2-hydroxy- MS (ES) 630.1 (M+1), MS (ES−)628.0 (M−1); ¹H ethyl NMR (400 MHz, CDCl₃) δ 7.86 (s, 1H), 7.66 (dd, 1H,J = 1.4, 7.8 Hz), 7.62 (s, 2H), 7.34 (dt, 1H, J = 1.0, 7.4 Hz), 7.26(dt, 1H, J = 2.0, 7.9 Hz), 7.12 (dd, 1H, J = 1.0, 7.9 Hz), 5.42 (s, 2H),4.07 (t, 2H, J = 6.0 Hz), 3.73 (m, 4H), 3.18 (t, 2H, J = 6.0 Hz), 3.00(m, 4H), 2.24 (br s, 1H). 84 dimethyl- hydroxy- MS (ES) 574.3 (M+H). ¹HNMR (400 MHz, CDCl₃) δ amino methyl 7.88 (s, 1H), 7.67 (dd, 1H, J = 7.7,1.9 Hz) 7.60 (s, 2H), 7.35 (dt, 1H, J = 8.0, 1.7 Hz), 7.29 (dt, 1H, J =7.7, 2.0 Hz), 7.15 (dd, 1H, J = 8.0, 1.3 Hz), 5.42 (s, 2H), 4.83 (br s,2H), 4.22 (br s, 1H), 2.78 (s, 6H). 85 dimethyl- 2-hydroxy- MS (ES)588.1 (M+H), 586.1 (M−H). ¹H NMR (400 amino ethyl MHz, CDCl₃) δ 7.87 (s,1H), 7.67 (dd, 1H, J = 7.8, 1.8 Hz), 7.60 (s, 2H), 7.33 (dt, 1H, J =7.9, 1.5 Hz), 7.27 (dt, 1H, J = 8.3, 1.8 Hz), 7.16 (dd, 1H, J = 8.3, 1.1Hz), 5.41 (s, 2H), 4.07 (dt, 2H, J = 6.7, 6.1 Hz), 3.20 (t, 2H, J = 6.1Hz), 2.78 (t, 1H, J = 6.7 Hz), 2.76 (s, 6H). 86 thio- 2-hydroxy- MS (ES)646.1 (M+H); ¹H NMR (400 MHz, CDCl₃) δ morpholino ethyl 7.88 (s, 1H),7.68 (dd, 1H, J = 7.7, 1.8 Hz), 7.62 (s, 2H), 7.36 dt, 1H, J = 8.0, 1.5Hz), 7.28 (dt, 1H, J = 7.7, 1.1 Hz), 7.15 (dd, 1H, J = 8.0, 1.1 Hz),5.40 (s, 2H), 4.09 (m, 2H), 3.25 (m, 4H), 3.19 (t, 2H, J = 6.3 Hz), 2.69(m, 4H). 87 morpholino methyl MS (ES+) 600.1 (M+1), MS (ES−) 598.0(M−1); ¹H NMR (400 MHz, CDCl₃) δ 7.89 (s, 1H), 7.65 (dd, 1H, J = 1.9,7.8 Hz), 7.63 (s, 2H), 7.33 (dt, 1H, J = 1.5, 8.0 Hz), 7.25 (dt, 1H, J =1.8, 7.4 Hz), 7.10 (dd, 1H, J = 1.1, 8.0 Hz), 5.42 (s, 2H), 3.73 (m,4H), 3.00 (m, 4H), 2.51 (s, 3H). 88 morpholino cyclo- MS (ES) 626.0(M+H). ¹H NMR (400 MHz, CHCl₃) δ propyl 7.88 (s, 1H), 7.65 (m, 3H), 7.33(dt, 1H, J = 7.8, 1.5 Hz), 7.25 (dt, 1H, J = 7.8, 1.5 Hz), 7.12 (dd, 1H,J = 7.8, 1.0 Hz), 5.44 (s, 2H), 3.75 (m, 4H), 3.04 (m, 4H), 2.32 (m,1H), 1.67 (m, 2H), 1.06 (m, 2H). 89 morpholino methoxy- MS (ES) 630.1(M+H). ¹H NMR (400 MHz, CHCl₃) δ methyl 7.81 (s, 1H), 7.70 (dd, 1H, J =7.3, 1.9 Hz), 7.68 (s, 2H), 7.31–7.40 (m, 2H), 7.22 (dd, 1H, J = 7.8,1.5 Hz), 5.49 (s, 2H), 4.77 (s, 2H), 3.74 (m, 4H), 3.33 (s, 3H), 3.01(m, 4H). 90 morpholino 2,2- MS (ES) 674.2 (M+H). ¹H NMR (400 MHz, CHCl₃)δ dimethoxy- 7.88 (s, 1H), 7.70 (dd, 1H, J = 7.8, 1.5 Hz), 7.66 (s,ethyl 2H), 7.36 (dt, 1H, J = 7.8, 1.5 Hz), 7.29 (dt, 1H, J = 7.8, 1.5Hz), 7.16 (dd, 1H, J = 7.8, 1.5 Hz), 5.46 (s, 2H), 4.81 (t, 1H, J = 5.7Hz), 3.75 (m, 4H), 3.31 (s, 6H), 3.30 (d, 2H, J = 5.7 Hz), 3.01 (m, 4H).91 dimethyl- methyl MS (ES) 558.1 (M+H), 556.1 (M−H). ¹H NMR (400 aminoMHz, CHCl₃) δ 7.86 (s, 1H), 7.64 (dd, 1H, J = 7.8, 1.9 Hz), 7.61 (s,2H), 7.32 (dt, 1H, J = 7.2, 1.6 Hz), 7.24 (dt, 1H, J = 7.2, 1.9 Hz),7.14 (dd, 1H, J = 7.8, 1.6Hz), 5.41 (s, 2H), 2.76 (s, 6H), 2.52 (s, 3H).92 dimethyl- methoxy- MS (ES) 588.2 (M+H). ¹H NMR (400 MHz, CHCl₃) δamino methyl 7.85 (s, 1H), 7.66 (dd, 1H, J = 7.4, 1.5 Hz), 7.64 (s, 2H),7.28–7.37 (m, 2H), 7.24 (m, 1H), 5.46 (s, 2H), 4.76 (s, 2H), 3.31 (s,3H), 2.74 (s, 6H). 93 dimethyl- 2,2- MS (ES) 632.1 (M+H). ¹H NMR (400MHz, CHCl₃) δ amino dimethoxy- 7.87 (s, 1H), 7.70 (dd, 1H, J = 7.8, 1.5Hz), 7.66 (s, ethyl 2H), 7.36 (dt, 1H, J = 7.8, 1.5 Hz), 7.29 (dt, 1H, J= 7.8, 1.5Hz), 7.16 (dd, 1H, J = 7.8, 1.5Hz), 5.46 (s, 2H), 4.81 (t, 1H,J = 5.7 Hz), 3.31 (s, 6H), 3.30 (d, 2H, J = 5.7 Hz), 2.76 (s, 6H). 94thio- hydroxy- MS (ES) 632.3 (M+H). ¹H NMR (400 MHz, CHCl₃) δ morpholinomethyl 7.89 (s, 1H), 7.67 (dd, 1H, J = 7.8, 1.7 Hz), 7.63 (s, 2H), 7.37(dt, 1H, J = 7.8, 1.7 Hz), 7.29 (dt, 1H, J = 7.8, 1.7 Hz), 7.15 (dd, 1H,J = 7.8, 1.0Hz), 5.42 (s, 2H), 4.83 (br s, 2H), 4.10 (br s, 1H), 3.26(m, 4H), 2.69 (m, 4H). 95 thio- methyl MS (ES) 616.1 (M+H), 614.1 (M−H).¹H NMR (400 morpholino MHz, CHCl₃) δ 7.87 (s, 1H), 7.67 (dd, 1H, J =7.8, 1.9) 7.63 (s, 2H), 7.36 (dt, 1H, J = 7.2, 1.6), 7.27 (dt, 1H, J =7.2, 1.9), 7.13 (dd, 1H, J = 7.8, 1.6), 5.41 (s, 2H), 3.26 (m, 4H), 2.69(m, 4H), 2.53 (s, 3H). 96 imidazol-1-yl hydroxy- MS [ES] 597.1 (M+H)⁺,595.1 (M−H)⁻. ¹H NMR (400 methyl MHz, CHCl₃) δ 7.91 (s, 1H), 7.74 (dd,1H, 1 7.6, 1.6 Hz) 7.70 (br s, 1H), 7.45–7.49 (m, 3H), 7.41 (dt, 1H, J =7.6, 2.0 Hz), 7.34 (br s, 1H), 7.21 (dd, 1H, J = 8.0, 1.2 Hz), 6.92 (brs, 1H), 5.42 (s, 2H), 4.83 (m, 2H), 3.00 (br s, 1H). 97 imidazol-1-ylmethyl MS [ES] 581.1 (M+H)⁺, 579.1 (M−H)⁻. ¹H NMR (400 MHz, CHCl₃) δ7.91 (s, 1H), 7.73 (dd, 1H, J = 7.7, 1.9 Hz) 7.60 (m, 1H), 7.41–7.45 (m,3H), 7.35 (dt, 1H, J = 8.3, 1.8 Hz), 7.32 (m, 1H), 7.17 (dd, 1H, J =8.3, 1.4 Hz), 6.92 (m, 1H), 5.38 (s, 2H), 2.50 (s, 3H). 98 imidazol-1-ylcyclo- MS (ES) 607.1 (M+H). ¹H NMR (400 MHz, CHCl₃) δ propyl 7.91 (s,1H), 7.71 (dd, 1H, J = 7.8, 1.0 Hz) 7.62 (s, 1H), 7.43 (s, 2H), 7.42 (t,1H, J = 7.8, 1.0 Hz), 7.34 (m, 2H), 7.17 (dd, 1H, J = 7.8, 1.0 Hz), 6.94(s, 1H), 5.38 (s, 2H), 2.29 (m, 1H), 1.14 (m, 2H), 1.05 (m, 2H). 99imidazol-1-yl methoxy- MS (ES) 611.2 (M+H). ¹H NMR (400 MHz, CHCl₃) δmethyl 7.89 (s, 1H), 7.72 (dd, 1H, J = 7.5, 2.1 Hz) 7.63 (s, 1H), 7.46(s, 2H), 7.37–7.45 (m, 2H), 7.29 (s, 1H), 7.25 (dd, 1H, J = 7.5, 1.4Hz), 6.91 (s, 1H), 5.45 (s, 2H), 4.75 (s, 2H), 3.33 (s, 3H). 1004-methyl- hydroxy- MS (ES) 629.3 (M+H). ¹H NMR (400 MHz, CHCl₃) δpiperazin-1- methyl 7.89 (s, 1H), 7.67 (dd, 1H, J = 7.7, 1.9 Hz), 7.65(s, yl 2H), 7.37 (dt, 1H, J = 7.7, 1.3Hz), 7.29 (dt, 1H, J = 7.7, 1.8Hz), 7.13 (dd, 1H, J = 7.7, 1.3 Hz), 5.42 (s, 2H), 4.82 (d, 2H, J = 7.4Hz), 4.18 (t, 1H, J = 7.4 Hz), 3.06 (br s, 4H), 2.48 (br s, 4H), 2.35(s, 3H). 101 4-methyl- methyl MS (ES) 613.2 (M+H), 611.2 (M−H). ¹H NMR(400 piperazin-1- MHz, CHCl₃) δ 7.87 (s, 1H), 7.63–7.65 (m, 3H) 7.33 yl(dt, 1H, J = 7.2, 1.6 Hz), 7.25 (dt, 1H, J = 7.2, 1.9 Hz), 7.13 (dd, 1H,J = 7.8, 1.6 Hz), 5.40 (s, 2H), 3.04 (m, 4H), 2.51 (s, 3H), 2.45 (m,4H), 2.32 (s, 3H). 102 4-isopropyl- hydroxy- MS (ES) 657.2 (M+H). ¹H NMR(400 MHz, CHCl₃) δ piperazin-1- methyl 7.89 (s, 1H), 7.64–7.68 (m, 3H),7.37 (m, 1H), 7.31 (dt, yl 1H, J = 7.4, 1.6Hz), 7.14(dd, 1H, J = 7.7,1.6Hz), 5.42 (s, 2H), 4.82 (m, 2H), 4.20 (br s, 1H), 3.04 (m, 4H), 2.74(s, 1H, J = 6.7 Hz), 2.55 (m, 4H), 1.05 (d, 6H, J = 6.7 Hz). 1034-isopropyl- 2-hydroxy- MS (ES) 671.2 (M+H). ¹H NMR (400 MHz, CHCl₃) δpiperazin-l- ethyl 7.87 (s, 1H), 7.65 (m, 1H), 7.63 (s, 2H), 7.33 (dt,1H, J = yl 8.1, 1.6 Hz), 7.27 (m, 1H), 7.14 (dd, 1H, J = 7.8, 1.6 Hz),5.40 (s, 2H), 4.06 (m, 2H), 3.19 (t, 2H, J = 5.8 Hz), 3.04 (br s, 4H),2.75 (m, 1H), 2.55 (br s, 4H), 1.04 (d, 6H, J = 7.0 Hz). 1044-carbamoyl- methyl MS [ES] 641.2 (M+H)⁺. ¹H NMR (400 MHz, CHCl₃)piperidin-1-yl δ 7.86 (s, 1H), 7.66 (m, 3H) 7.34 (dt, 1H, J = 7.3, 1.5Hz), 7.25 (m, 1H), 7.12 (dd, 1H, J = 8.0, 1.0 Hz), 5.37– 5.47 (m, 4H),3.33 (dt, 2H, J = 11.7, 2.3 Hz), 2.81 (m, 2H), 2.53 (s, 3H), 2.37–2.44(m, 1H), 1.79–1.97 (m, 4H).

Example 105[1-(3,5-Bis-trifluoromethyl-benzyl)-5-dimethylamino-1H-[1,2,3]triazol-4-yl]-[4-(2-chloro-phenyl)-3-(2-hydroxy-ethyl)-isoxazol-5-yl]-methanone

Following a method similar to General Example F, the title compound maybe prepared and isolated. MS [ES] 588.1 (M+H)⁺, 586.1 (M−H)⁻; ¹H NMR(400 MHz, CHCl₃) δ 7.87 (s, 1H), 7.71 (s, 2H), 7.37 (m, 1H), 7.26–7.32(m, 3H), 5.50 (s, 2H), 3.93 (m, 2H), 2.87 (m, 2H), 2.74 (s, 6H).

By the method of General Example F, the following compounds may beprepared and isolated.

Ex. # R⁵ R⁷ Physical Data 106 morpholino hydroxy- MS (ES) 616.0 (M+1);TLC R_(f) = 0.1 (50% methyl EtOAc in hexanes). 107 4-methyl- hydroxy- MS(ES) 629.1 (M⁺+1); TLC R_(f) = 0.3 (5% piperazin-1-yl methyl MeOH indichloromethane). 108 dimethyl-amino hydroxy- MS (ES) 574.0 (M⁺+1);TLC): R_(f) = 0.4 (50% methyl EtOAc in hexanes 109 (2-dimethyl- hydroxy-MS (ES) 631.l(M⁺+l); TLC R_(f) = 0.2 (5% amino-ethyl)- methyl MeOH indichloromethane). methyl-amino 110 thio-morpholino hydroxy- MS (ES)632.0 (M⁺+1); TLC R_(f) = 0.2 (50% methyl EtOAc in hexanes). 111morpholino 2- MS (ES) 698.9 (M⁺+1); TLC R_(f) = 0.1 (5% (morpholino)-MeOH in dichloromethane). ethyl 112 imidazol-1-yl hydroxy- MS (ES) 597.1(M⁺+1); TLC R_(f) = 0.1 (elute methyl with 20% then 25% acetone inhexanes). 113 morpholino hydrogen MS (ES) 586.2 (M⁺+1); TLC R_(f) = 0.1(50% ether in hexanes). 114 imidazol-1-yl hydrogen MS (ES) 586.2 (M⁺+1);TLC R_(f) = 0.1 (50% ether in hexanes). 115 morpholino methoxy- m.p.119° C.; TLC: R_(f) = 0.15 (2:1 methyl hexanes/EtOAc) MS(ES) 629.9 (M+1)

By the method of General Example F, the following compounds may beprepared and isolated.

Ex. # R⁵ Physical Data 116 morpholino MS (ES+) 586.0 (M+1)⁺, MS (ES−)584.0 (M−1). ¹H NMR (400 MHz, CDCl₃) δ 14.68 (br s, 1H), 7.87 (s, 1H),7.84 (s, 2H), 7.54 (m, 1H), 7.46 (m, 1H), 7.38 (m, 2H), 5.64 (s, 2H),3.74 (m, 4H), 2.99 (m, 4H). 117 dimethyl- MS (ES) 544.0 (M+H), 542.0(M−H). ¹H NMR (400 MHz, CHCl₃) δ amino 7.88 (s, 1H), 7.82 (s, 2H) 7.56(m, 1H), 7.46 (m, 1H), 7.38 (m, 2H), 5.62 s, 2H, 2.75 s, 6H. 1184-methyl- MS [ES] 599.1 (M+H). ¹H NMR (400 MHz, CHCl₃) δ 7.89 (s, 1H),piperazin-1- 7.85 (s, 2H), 7.54 (m, 1H), 7.44 (m, 1H), 7.33–7.40 (m,2H), 5.61 (s, yl 2H), 3.04(brs, 4H), 2.48(brs, 4H), 2.33(s, 3H).

By the method of General Example F, the following compounds may beprepared and isolated.

Ex. # R⁵ Physical Data 119 morpholino MS (ES) 585.1 (M+H). ¹H NMR (400MHz, CHCl₃) δ 13.25 (br s, 1H), 7.89 (s, 1H), 7.86 (s, 2H), 7.60 (s,1H), 7.46 (m, 1H), 7.38 (m, 1H), 7.30–7.32 (m, 2H), 5.65 (s, 2H), 3.75(m, 4H), 2.99 (m, 4H). 120 dimethyl-amino MS [ES] 543.1 (M+H)⁺. ¹H NMR(400 MHz, CHCl₃) δ 13.25 (br s, 1H), 7.89 (s, 1H), 7.83 (s, 2H), 7.67(s, 1H), 7.46 (m, 1H), 7.38 (m, 1H), 7.30–7.32 (m, 2H), 5.59 (s, 2H),2.72 (s, 6H). 121 4-methyl- MS [ES] 598.2 (M+H)⁺, 596.1 (M−H)⁻. ¹H NMR(400 MHz, piperazin-1-yl CHCl₃) δ 13.25 (br s, 1H), 7.89 (s, 1H), 7.86(s, 2H), 7.66 (s, 1H), 7.43 (m, 1H), 7.36 (m, 1H), 7.27–7.30 (m, 2H),5.59 (s, 2H), 3.00 (br s, 4H), 2.45 (br s, 4H), 2.31 (s, 3H). 122thio-morpholino MS [ES] 601.0 (M+H)⁺. ¹H NMR (400 MHz, CHCl₃) δ 7.89 (s,1H), 7.83 (s, 2H), 7.68 (s, 1H), 7.47 (m, 1H), 7.38 (m, 1H), 7.31– 7.33(m, 2H), 5.59 (s, 2H), 3.23 (m, 4H), 2.69 (m, 4H).

By the method of General Example F, the following compounds may beprepared and isolated.

Ex. # R⁵ Physical Data 123 morpholino MS [ES] 585.1 (M+H)⁺. ¹H NMR (400MHz, CHCl₃) δ 8.84 (s, 1H), 7.88 (s, 1H), 7.83 (s, 2H), 7.48 (m, 1H),7.43 (m, 1H), 7.33–7.40 (m, 2H), 5.58 (s, 2H), 3.73 (m, 4H), 2.97 (m,4H). 124 dimethyl- MS [ES] 542.9 (M)⁺. ¹H NMR (400 MHz, CHCl₃) δ 11.67(br s, 1H), amino 8.77 (s, 1H), 7.86 (s, 1H), 7.81 (s, 2H), 7.47 (m,1H), 7.42 (m, 1H), 7.32–7.36 (m, 2H), 5.54 (s, 2H), 2.68 (s, 6H). 125thio- MS [ES] 601.1 (M+H)⁺. ¹H NMR (400 MHz, CHCl₃) δ 8.70 (s, 1H),morpholino 7.88 (s, 1H), 7.80 (s, 2H), 7.48 (m, 1H), 7.43 (m, 1H),7.33–7.37 (m, 2H), 5.53 (s, 2H), 3.20 (m, 4H), 2.65 (m, 4H).

By the method of General Example F, the following compounds may beprepared and isolated.

Ex. # R⁵ R⁷ Physical Data 126 morpholino methyl MS (ES) 600.2 (M+1),(ES) 598.2 (M−1). ¹H NMR (400 MHz, CDCl₃) δ 7.86 (s, 1H), 7.72 (s, 2H),7.55 (dd, 1H, J = 1.5, 7.4Hz), 7.30 (dt, 1H, J = 1.3, 7.3 Hz), 7.23 (dt,1H, J = 1.9, 7.4 Hz), 7.17 (dd, 1H, J = 1.1, 7.8 Hz), 5.47 (s, 2H), 3.71(m, 4H), 2.98 (m, 4H), 2.64 (s, 3H). 127 morpholino isopropyl MS (ES)628.2 (M+H). ¹H NMR (400 MHz, CHCl₃) δ 7.88 (s, 1H), 7.72 (s, 2H), 7.60(dd, 1H, J = 7.8, 1.4 Hz), 7.31 (dt, 1H, J = 7.8, 1.4 Hz), 7.22 (dt, 1H,J = 7.8, 1.4 Hz), 7.14 (dd, 1H, J = 7.8, 1.4Hz), 5.48 (s, 2H), 3.73 (m,4H), 3.26 (s, 1H, J = 6.7 Hz), 3.01 (m, 4H), 1.46 (d, 6H, J = 6.7 Hz).128 morpholino cyclo- MS [ES] 626.1 (M+H)⁺. ¹H NMR (400 MHz, CHCl₃)propyl δ 7.88 (s, 1H), 7.72 (s, 2H), 7.55 (dd, 1H, J = 7.3, 1.4 Hz),7.31 (dt, 1H, J = 7.3, 1.4 Hz), 7.22 (dt, 1H, J = 7.3, 1.4 Hz), 7.16(dd, 1H, J = 7.8, 1.4 Hz), 5.48 (s, 2H), 3.73 (m, 4H), 3.00 (m, 4H),2.24 (m, 1H), 1.17– 1.34 (m, 4H). 129 imidazol- methyl MS (ES) 581.1(M+H), ¹H NMR (400 MHz, CDCl₃) 1-yl δ 7.90 (s, 1H), 7.72 (s, 1H) 7.56(m, 3H), 7.28–7.37 (m, 4H), 6.94 (s, 1H), 5.50 (s, 2H), 2.65 (s, 3H).130 imidazol- isopropyl MS (ES) 609.1 (M+H). ¹H NMR (400 MHz, CHCl₃)1-yl δ 7.89(s, 1H), 7.68(s, 1H) 7.58 (dd, 1H, J = 7.5, 1.7 Hz), 7.52 (s,2H), 7.22–7.36 (m, 4H), 6.94 (s, 1H), 5.46 (s, 2H), 3.25 (s, 1H, J = 6.9Hz), 1.45 (d, 6H, J = 6.9 Hz).

Example 131[1-(3,5-Bis-trifluoromethyl-benzyl)-5-imidazol-1-yl-1H-[1,2,3]triazol-4-yl]-[4-(2-chloro-phenyl)-2-cyclopropyl-oxazol-5-yl]-methanone

Add imidazole (0.37 g, 5.44 mmol) to a solution of[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazol-4-yl]-[4-(2-chloro-phenyl)-2-cyclopropyl-oxazol-5-yl]-methanone(0.16 g, 0.28 mmol) in DMSO (1.0 mL) and heat to 80° C. for 18 h. Dilutereaction mixture with EtOAc and wash with water and brine, then dry,filter, and concentrate. Purify by flash chromatography using a lineargradient of 30% to 70% EtOAc in hexane to give the title compound (0.15g, 76%). MS (ES) 607.1 (M+H). ¹H NMR (400 MHz, CHCl₃) δ 7.88 (s, 1H),7.61 (s, 1H) 7.51 (m, 3H), 7.21–7.33 (m, 4H), 6.92 (s, 1H), 5.43 (s,2H), 2.20 (m, 1H), 1.17–1.31 (m, 4H).

Example 132[1-(3,5-bis-trifluoromethyl-benzyl)-5-(1,1-dioxo-1λ-thiomorpholin-4-yl)-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-3-(2-hydroxy-ethyl)-isoxazol-4-yl]-methanone

Combine[1-(3,5-bis-trifluoromethyl-benzyl)-5-(thiomorpholin-4-yl)-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-3-hydroxymethyl-isoxazol-4-yl]-methanone(0.17 g, 0.26 mmol) in dichloromethane (3.0 mL), add3-chloroperoxybenzoic acid (0.12 g, 0.50 mmol) and stir at RT. After 2h., dilute with EtOAc, wash with 1N NaOH, water and brine, dry, filter,and concentrate. Purify by flash chromatography using a linear gradientof 50% to 80% EtOAc in hexane to give the title compound. MS (ES) 678.0(M+H). ¹H NMR (400 MHz, CD₃COCD₃) δ 8.09(s, 1H), 7.99 (s, 2H), 7.65 (m,1H), 7.42 (m, 2H), 7.35 (m, 1H), 5.86 (s, 2H), 3.89 (m, 3H), 3.62 (m,4H), 3.26 (m, 4H), 3.14 (m, 2H).

By a method similar to Example 132, the following compounds may beprepared and isolated.

Ex. # R⁷ Physical Data 133 hydroxy- MS (ES) 664.0 (M+H). ¹H NMR (400MHz, CHCl₃) δ 7.92 (s, 1H), methyl 7.74 (dd, 1H, J = 7.8, 1.6 Hz) 7.61(s, 2H), 7.44 (dt, 1H, J = 7.8, 1.6 Hz), 7.36 (dt, 1H, J = 7.8, 1.6 Hz),7.18 (dd, 1H, J = 8.1, 0.9 Hz), 5.48 (s, 2H), 4.85 (d, 2H, J = 6.6 Hz),3.75 (t, 1H), 3.55 (m, 4H), 3.15 (m, 4H). 134 methyl MS [ES] 648.1(M+H)⁺, 646.0 (M−H). ¹H NMR (400 MHz, CHCl₃) δ 7.91 (s, 1H), 7.73 (dd,1H, J = 7.7, 1.9 Hz) 7.62 (s, 2H), 7.41 (m, 1H), 7.31 (dt, 1H, J = 7.9,2.2 Hz), 7.15 (m, 1H), 5.47 (s, 2H), 3.56 (m, 4H), 3.15 (m, 4H), 2.53(s, 3H).

By a method analogous to Example 132, the following compounds may beprepared and isolated.

Ex. # n R⁷ Physical Data 135 1 hydroxy-methyl MS (ES) 648.0 (M⁺+1); TLCR_(f) = 0.2 (acetone). 136 2 hydroxy-methyl MS (ES) 664.0 (M⁺+1); TLCR_(f) = 0.1 (60% EtOAc in hexanes). 137 2 2-hydroxy-ethyl MS (ES) 645.9(M⁺+1); TLC R_(f) = 0.1 (50% EtOAc in hexanes).

Example 138[1-(3,5-bis-trifluoromethyl-benzyl)-5-(1,1-dioxo-1λ-thiomorpholin-4-yl)-1H-[1,2,3]triazol-4-yl]-[4-(2-chloro-cyclohexa-2,4-dienyl)-2H-pyrazol-3-yl]-methanone

Using the method of Example 132, with the appropriate startingmaterials, the title compound can be prepared and isolated. MS [ES]633.0 (M+H)⁺. ¹H NMR (400 MHz, CD₃COCD₃) δ 13.4 (br s, 1H), 8.10 (s,2H), 8.04 (s, 1H), 7.64 (br s, 1H), 7.38 (m, 2H), 7.28 (m, 2H), 5.93 (s,2H), 3.55 (m, 4H), 3.20 (m, 4H).

Example 139[1-(3,5-bis-trifluoromethyl-benzyl)-5-(1-oxo-1λ-thiomorpholin-4-yl)-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-3-methyl-isoxazol-4-yl]-methanone

Add 30% aqueous hydrogen peroxide (2.0 mL, excess) to a solution of[1-(3,5-bis-trifluoromethyl-benzyl)-5-thiomorpholin-4-yl-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-3-methyl-isoxazol-4-yl]-methanone(0.9 g, 0.15 mmol) in MeOH (4.0 mL) and stir at RT for 24 h. Dilutereaction mixture with water, extract with EtOAc, then dry, filter, andconcentrate. Purify by flash chromatography using a linear gradient of2% to 4% MeOH in dichloromethane to give the title compound (15 mg,16%). MS [ES] 632.1 (M+H)⁺, 630.1 (M−H)⁻. ¹H NMR (400 MHz, CHCl₃) δ 7.90(s, 1H), 7.71 (dd, 1H, J=7.8, 1.9 Hz) 7.62 (s, 2H), 7.38 (dt, 1H, J=7.9,1.6 Hz), 7.31 (dt, 1H, J=7.9, 1.9 Hz), 7.15 (dd, 1H, J=7.8, 1.6 Hz),5.45 (s, 2H), 3.83 (m, 2H), 3.10 (m, 2H), 2.87–2.96 (m, 4H), 2.52 (s,3H).

General Example G

In a pressure vessel, dissolve the alkyne of interest (1 eq.) in toluene(0.1 M), add the azide of interest (2 eq.), and place in a 120 IC bath.After 48 h., concentrate and purify by chromatography on silica gel.Trimethylsilyl azide may be used to prepare unsubstituted triazoles.

By the method of General Example G, the following compounds may beprepared and isolated.

Ex. # R⁷ R^(b) Physical Data 140 hydrogen 2-chloro MS (ES) 577.2 (M+1),¹H NMR (300 MHz, CDCl₃): δ 7.89 (s, 1H), 7.62–7.25 (m, 12H), 5.68 (s,2H). 141 hydrogen hydrogen MS (ES) 543.3 (M+1), ¹H NMR (300 MHz, CDCl₃):δ 7.99 (ap q, 1H), 7.89 (s, 1H), 7.66–7.23 (m, 11H), 5.67 (s, 2H). 142hydrogen 4-fluoro MS (ES) 561.3 (M+1), ¹H NMR (300 MHz, CDCl₃): δ 8.04(m, 1H), 7.88 (s, 1H), 7.68–7.09 (m, 11H), 5.67 (s, 2H). 143 hydrogen 3-MS (ES) 611.3 (M+1), δ 8.19 (m, 1H), 8.11 (d, J = 7.8 trifluoro- Hz,1H), 7.76 (s, 1H), 7.60–7.13 (m, 9H), 5.56 (s, 2H). methyl 144 hydrogen2-fluoro MS (ES 561.3 (M+1), δ 7.75 (s, 1H), 7.61–6.96 (m, 11H), 5.54(s, 2H). 145 2-pyrrolidin- 2-chloro MS (ES) 674.2 (M+1), TLC (50%EtOAc/Hexane), R_(f) = 1-yl-ethyl 0.59 146 ([1,3]- 2-chloro MS (ES)663.6 (M+1), ¹H NMR (300 MHz, CDCl₃): δ dioxalan-2- 7.82 (s, 1H),7.51–7.37 (m, 9H), 7.22 (m, 2H), 5.58 (s, yl)-methyl 2H), 5.28 (ab q,1H), 4.54 (dd, J = 14.5, 3.2 Hz, 1H), 4.18 (dd, J = 14.5, 5.0 Hz, 1H),3.83–3.63 (m, 4H).

By the method of General Example G, the following compounds may beprepared and isolated.

Ex. # R⁷ Physical Data 147 2-pyrrolidin-1-yl- MS (ES) 674.2 (M+1); TLCR_(f) = 0.59 (50% EtOAc/Hexane). ethyl 148 ([1,3]-dioxalan- MS (ES)663.6 (M+1), ¹H NMR (300 MHz, CDCl₃): δ 7.85 (br s, 2-yl)-methyl 1H),7.78 (dd, J = 7.7, 1.6 Hz, 1H), 7.61–7.49 (m, 3H), 7.41–7.10 (m, 7H),5.46 (s, 2H), 5.32 (t, J = 3.0 Hz, 1H), 4.97 (d, J = 3.0 Hz, 2H), 3.70(m, 4H).

By the method of General Example G, the following compounds may beprepared and isolated.

Ex. # R⁵ Physical Data 149 pyridin-3-yl Exact Mass 577.09; MS (ESI) m/z576.3 (M−1). ¹H NMR (300 MHz, CDCl₃) δ 5.66 (s, 2H), 7.30–7.56 (m, 8H),7.84 (s, 1H), 8.54 (d, 1H, J = 1.87 Hz), 8.76 (m, 1H) 150 pyridin-4-ylExact Mass 577.09, MS (ESI) m/z 576.3 (M−1); ¹H NMR (300 MHz, CDCl₃) δ5.61 (s, 2H), 7.16 (d, J = 5.85 Hz, 2H), 7.34 (m, 2H), 7.42 (m, 1H),7.50 (m, 3H), 7.87 (s, 1H), 8.77 (d, 2H, J = 5.66 Hz). 151 methyl MS[ES] 515.1 (M+H)⁺, 513.1 (M−H)⁻; ¹H NMR (400 MHz, CHCl₃) δ 15.25 (br s,1H), 7.90 (s, 1H), 7.71 (s, 2H), 7.48–7.57 (m, 2H), 7.35– 7.44 (m, 2H),5.74 (s, 2H), 2.61 (s, 3H).

Example 152[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-1-(2-hydroxy-ethyl)-1H-[1,2,3]thiazol-4-yl]-methanone

Dissolve[1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-[1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-(2-chloro-phenyl)-1H-[1,2,3]triazol-4-yl]-methanone(0.43 g, 0.58 mmol) in THF (5 mL, 0.2 M), add t-butyl ammonium flouride(0.88 mL of a 1M soln. in THF, 1.5 eq.), and stir at RT. When thereaction is complete, concentrate and purify by chromatography on silicagel. MS (ES) 621.0 (M+1); ¹H NMR (300 MHz, CDCl₃): δ 7.82 (s, 1H),7.53–7.19 (m, 11H), 5.59 (s, 2H), 4.40–3.98 (s, 4H), 2.06 (br s, 1H).

Example 153[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-3-(2-hydroxy-ethyl)-3H-[1,2,3)triazol-4-yl]-methanone

Using a method similar to Example 152, the title compound may beprepared and isolated. MS (ES) 621.0 (M+1); ¹H NMR (300 MHz, CDCl₃): δ7.86–7.09 (m, 12H), 5.44 (s, 2H), 4.80 (t, J=5.0 Hz, 2H), 4.16 (m, 2H),2.56 (t, J=6.0 Hz, 1H).

General Example H

Add Dess-Martin periodinane (1.5 eq.) to a solution of the appropriatealcohol (1 eq.) in dichloromethane (0.05M–0.5M). Stir at 0° C. for 30min., then at RT for 1–5 h. Dilute with ether and wash with cold 0.1NNaOH, water, and brine. Dry, filter, and concentrate the organic phaseand purify the crude material by flash chromatography to give the titlecompound.

Alternatively, under N₂, charge an oven-dried flask with oxalyl chloride(2M in CH₂Cl₂, 1.2 eq.) and chill in a dry ice/acetone slush. Add DMSO(3 eq.) slowly by syringe and stir 15 min. Add the alcohol of interest(1 eq.) in anhydrous CH₂Cl₂ (0.4 M) slowly by syringe and stir 1 h. AddTEA (5 eq.) slowly by syringe and stir 2 h. while bath is allowed toexpire. Quench with H₂O, extract with ether, dry over MgSO₄, filter andconcentrate under vacuum to give the title compound.

Using one of the methods of General Example H, the following compoundsare prepared and isolated.

Ex. # R⁵ R⁷ Physical Data 154 morpho- —CHO MS (ES) 614.0 (M+1), MS (ES−)612.0 (M−1); ¹H NMR lino (400 MHz, CDCl₃) δ 10.15 (s, 1H), 7.87 (s, 1H),7.69 (s, 2H), 7.67 (m, 1H), 7.41 (m, 3H), 5.54 (s, 2H), 3.72 (m, 4H),3.01 (m,, 4H). 155 morpho- —CH₂— MS (ES) 628.1 (M+1), MS (ES−) 626.0(M−1); ¹H NMR lino CHO (400 MHz, CDCl₃) δ 9.82 (t, 1H, J = 1.0 Hz), 7.86(s, 1H), 7.70 (dd, 1H, J = 1.9, 7.8 Hz), 7.63 (s, 2H), 7.38 (dt, 1H, J =1.3, 7.8 Hz), 7.31 (dt, 1H, J = 1.9, 7.8 Hz), 7.16 (dd, 1H, J = 1.0, 7.8Hz), 5.43 (s, 2H), 4.10 (d, 2H, J = 1.0 Hz), 3.72 (m, 4H), 2.97 (m, 4H).156 dimethyl- —CHO MS (ES) 572.1 (M+H), 570.1 (M−H). ¹H NMR (400 MHz,amino CDCl₃) δ 10.21 (s, 1H), 7.89 (s, 1H), 7.68 (m, 1H), 7.60 (s, 2H),7.38–7.46 (m, 3H), 5.52 (s, 2H), 3.44 (s, 6H). 157 thio- —CH₂— MS (ES)572.1 (M+H), 570.1 (M—H). ¹H NMR (400 MHz, morpho- CHO CDCl₃) δ 9.81 (s,1H), 7.92 (s, 1H), 7.74 (dd, 1H, J = 7.8, line-1,1- 1.5 Hz), 7.60 (s,2H), 7.45 (dt, 1H, J = 7.8, 1.5 Hz), 7.38 dioxide (dt, 1H, 7.8, 1.5 Hz),7.21 (dd, 1H, J = 7.8, 1.5 Hz), 5.48 (s, 2H), 4.18 (s, 2H), 3.53 (m,4H), 3.12 (m, 4H). 158 methyl —CHO MS (ES) 543.0 (M+H), 541.0 (M−H); ¹HNMR (400 MHz, CDCl₃) δ 10.21 (s, 1H), 7.89 (s, 1H), 7.68 (m, 1H), 7.60(s, 2H), 7.38–7.46 (m, 3H), 5.60 (s, 2H), 2.58 (s, 3H). 159 methyl —CH₂—MS (ES) 556.9 (M+1), MS (ES−) 554.9 (M−1); ¹H NMR CHO (400 MHz, CDCl₃) δ9.83 (s, 1H), 7.87 (s, 1H), 7.70 (dd, 1H, J = 2.0, 7.8), 7.52 (s, 2H),7.36 (m, 2H), 7.22 (m, 1H), 5.50 (s, 2H), 4.08 (s, 2H), 2.49 (s, 3H).160 pyridin-4-yl —CHO MS (ES) 606.0 (M+1); ¹H NMR (400 MHz, CDCl₃) δ10.17 (s, 1H), 8.74 (m, 2H), 7.84 (s, 1H), 7.65 (m, 1H), 7.44 (s, 2H),7.42 (m, 1H), 7.38 (m, 2H), 7.21 (m, 2H), 5.56 (s, 2H). 161 phenyl —CHOMS (ES) 605.0 (M+1); ¹H NMR (300 MHz, CDCl₃): δ 10.11 (s, 1H), 7.74 (s,1H), 7.62–7.10 (m, 11H), 5.48 (s, 2H). 162 pyrazin-2-yl —CHO TLC R_(f)0.54 (EtOAc); ¹H NMR (300 MHz, CDCl₃): δ 10.20 (s, 1H), 9.07 (s, 1H),8.67 (m, 2H), 7.81 (s, 1H), 7.67 (m, 3H), 7.43 (m, 3H), 5.93 (s, 2H).

General Example I

Dissolve the acetal of interest (1 eq.) in acetone/H₂O (4:1) and addp-toluenesulfonic acid (1 eq). Attach a reflux condenser and heat themixture overnight at 60° C. Neutralize with saturated aqueous NaHCO₃,extract with EtOAc, dry over MgSO₄, filter, and concentrate undervacuum.

Alternatively, in a pressure vessel, dilute the acetal of interest (1eq) with acetic acid/H₂O (2:1, 0.1 M) and heat at 125° C. for 48 h.Concentrate the mixture and dissolve the residue in EtOAc. Wash withsaturated aqueous NaHCO₃ and brine, then dry the organic layer overMgSO₄, filter, and concentrate under vacuum.

Using one of the above methods and the appropriate starting materials,the following compounds may be prepared and isolated.

Ex. # R⁵ Physical Data 163 phenyl MS (ES) 619.0 (M+1), ¹H NMR (300 MHz,CDCl₃): δ 9.82 (s, 1H), 7.84 (s, 1H), 7.76 (m, 1H), 7.59–7.19 (m, 10H),5.45 (s, 2H), 4.10 (d, J = 1.3 Hz, 2H). 164 pyrazin-2-yl MS (ES) 621.1(M+1), TLC (50% EtOAc/Hexane × 3), R_(f) = 0.30.

By the methods of General Example I, the following compounds may beprepared and isolated.

Ex. # R⁵ Physical Data 165 phenyl MS (ES) 619.0 (M+1), ¹H NMR (300 MHz,CDCl₃): δ 9.70 (s, 1H), 7.87–7.07 (m, 12H), 5.49(s, 2H), 5.43(s, 2H).166 pyridin-3-yl TLC R_(f) 0.04 (75% EtOAc/Hexane), ¹H NMR (300 MHz,CDCl₃): δ 9.60 (s, 1H) indicates aldehyde 167 pyridin-4-yl TLC R_(f)0.07 (75% EtOAc/Hexane), ¹H NMR (300 MHz, CDCl₃): δ 9.61 (s, 1H)indicates aldehyde 168 pyrazin-2-yl TLC R_(f) 0.07 (50% EtOAc/Hexane),¹H NMR (300 MHz, CDCl₃): δ 9.75 (s, 1H) indicates aldehyde

General Example J

Combine the appropriate alcohol (1.0 eq.) in dichloromethane, addDess-Martin periodinane (2.0 eq.) and allow the mixture to stir at RT.After 1 h., concentrate in vacuo and dilute the residue with ether andwash with saturated aqueous sodium bicarbonate solution, dry the organiclayer with anhydrous MgSO₄, filter and concentrate in vacuo. Purify bychromatography on silica gel to give the title compound.

By the method of General Example J, the following compounds may beprepared and isolated.

Ex. # R⁵ Physical Data 169 morpholino MS (ES) 614.1 (M+1); TLC (50%ether in hexanes): R_(f) = 0.1. 170 phenyl MS ES 605.0 (M+1); TLC (33%EtOAc in hexanes): R_(f) = 0.1.

Example 171[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-3-(1-hydroxy-ethyl)-isoxazol-4-yl]-methanone

To a solution of4-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carbonyl]-5-(2-chloro-phenyl)-isoxazole-3-carbaldehyde(75 mg, 0.12 mmol) in THF (0.6 mL) at −78° C. under N₂, addmethylmagnesium bromide (120 μL, 3.0 M in Et₂O). Allow the reaction towarm to 0° C. and stir for two h., then quench the reaction with asaturated solution of NH₄Cl (1 mL). Dilute the mixture with CH₂Cl₂ (1mL), wash with H₂O (1 mL) and brine (1 mL). Pass the organic layerthrough a Varian ChemElute® drying cartridge and concentrate. Purify theresidue by chromatography on silica gel using a gradient of 10:1Hex/EtOAc to 2:1 Hex/EtOAc to afford the title compound (4.3 mg, 6%).MS/ES (M+1)=620.9.

Example 172[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-[3-(2-chloro-6-fluorophenyl)-5-methyl-isoxazol-4-yl]-methanone

Heat a mixture of3-(2-chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl chloride (187mg, 0.681 mmol) and1-(3,5-bis-trifluoromethyl-benzyl)-4-(tri-n-butylstannanyl)-5-phenyl-1H-[1,2,3]triazole(300 mg, 0.454 mmol) in the presence of PdCl₂(PPh₃)₂ (32 mg) in degassed1,4-dioxane (3.0 mL) at 80° C. After 18 h., concentrate in vacuo andpurify the residue by chromatography on silica gel to provide the titlecompound (50% yield) as a light yellow foam. MS (ES) 609.0 (M⁺+1); TLCR_(f)=0.1 (6% acetone in hexanes).

By a method analogous to Example 172, the following compounds may beprepared and isolated.

Ex. # R^(b) Physical Data 173 2-chloro MS (ES) 591.0 (M⁺+1); TLC R_(f) =0.1 (10% acetone in hexanes). 174 2,6-dichloro MS ES 625.0 (M⁺+1); TLCR_(f) = 0.1 (6% acetone in hexanes).

Example 175[1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazol-4-yl]-[5-chloromethyl-3-(2-chloro-phenyl)-isoxazol-4-yl]-methanone

Add N,N-dimethylaminopyridine (119 mg, 0.974 mmol), p-toluenesulfonylchloride (465 mg, 2.44 mmol) and triethylamine into an ice-cold solutionof[1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazol-4-yl]-[3-(2-chlorophenyl)-5-hydroxymethyl-isoxazol-4-yl]-methanone(1.0 g, 1.62 mmol) in dichloromethane (5.0 mL) and THF (5.0 mL). Warmthe mixture to RT. After 1 h., concentrate in vacuo. Dilute the mixturewith dichloromethane (50 mL) and wash with water (3×40 mL). Dry (MgSO₄),filter, and concentrate in vacuo. Purify the residue by flashchromatography on silica gel to provide the title compound (59% yield)as a brown oil. MS (ES) 634.1 (M⁺+1); TLC R_(f)=0.5 (50% EtOAc inhexanes).

Example 176[1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazol-4-yl]-[3-(2-chloro-phenyl)-5-morpholin-4-ylmethyl-isoxazol-4-yl]-methanone

Heat a mixture of[1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazol-4-yl]-[5-chloromethyl-3-(2-chloro-phenyl)-isoxazol-4-yl]-methanone(100 mg, 0.158 mmol), triethylamine (80 mg, 0.790 mL) and morpholine(0.79 mL) at 50° C. for 18 h. Cool to RT, dilute the mixture withdichloromethane (50 mL) and wash with water (4×40 mL). Dry the organiclayer with anhydrous MgSO₄, filter, and concentrate in vacuo. Purify theresidue by flash chromatography on silica gel to give the title compound(93% yield) as a brown oil. MS (ES) 685.2 (M⁺+1); TLC R_(f)=0.1 (75%EtOAc in hexanes).

Example 177[1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazol-4-yl]-[3-(2-chloro-phenyl)-5-dimethylaminomethyl-isoxazol-4-yl]-methanone

Using a method similar to Example 176, the title compound may beprepared and isolated. MS (ES) 643.2 (M⁺+1); TLC R_(f)=0.1 (75% EtOAc inhexanes).

Example 1781-[4-[1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazole-4-carbonyl]-3-(2-chloro-phenyl)-isoxazol-5-yl]-ethanone

Add Dess-Martin periodinane (27.0 mg, 0.064 mmol) to a solution of[1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazol-4-yl]-[3-(2-chloro-phenyl)-5-(1-hydroxy-ethyl)-isoxazol-4-yl]-methanone(20.0 mg, 0.032 mmol). Stir at RT for 1 h., then concentrate in vacuoand dilute the residue with ether and wash with saturated aqueous sodiumbicarbonate solution. Dry the organic layer with anhydrous MgSO₄,filter, and concentrate in vacuo. Purify the residue by flashchromatography on silica gel to provide the title compound (99% yield)as a brown oil. MS (ES) 628.1 (M⁺+1); TLC R_(f)=0.1 (50% EtOAc inhexanes).

Example 179[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-{3-(2-chloro-phenyl)-5-[(2-morpholin-4-yl-ethylamino)-methyl]-isoxazol-4-yl}-methanone

Add 4-(2-aminoethyl)-morpholine (129 mg, 0.992 mmol) to a solution of4-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carbonyl]-3-(2-chloro-phenyl)-isoxazole-5-carbaldehyde(150 mg, 0.248 mmol) in 1,2-dichloroethane (2.5 mL). Then add NaBH(OAc)₃(157 mg, 0.744 mmol) and allow the mixture to stir at RT. After 3 h.,quench the reaction with water and extract with EtOAc (2×50 mL). Dry theorganic layer over MgSO₄, filter, and concentrate in vacuo. Purify theresidue by flash chromatography on silica gel to provide the titlecompound (61% yield) as a brown oil. MS (ES) 720.1 (M⁺+1); TLC R_(f)=0.1(EtOAc).

By a method analogous to Example 179, the following compounds may beprepared and isolated.

Ex. # R⁵ R⁷ Physical Data 180 phenyl isopropyl- MS (ES) 648.0 (M+1), ¹HNMR (300 MHz, CDCl₃): amino-methyl δ 7.74 (s, 1H), 7.63–7.10 (m, 11H),5.36 (s, 2H), 3.98 (s, 2H), 2.73 (m, 1H), 0.93 (d, J = 6.3 Hz, 6H). 181phenyl morpholino- MS (ES) 676.0 (M+1), ¹H NMR(300 MHz, CDCl₃): methyl δ7.84 (s, 1H), 7.72–7.22 (m, 11H), 5.53 (s, 2H), 3.88 (s, 2H), 3.48 (m,4H), 2.43 (m, 4H). 182 phenyl dimethyl- MS (ES) 634.1 (M+1), ¹H NMR (300MHz, CDCl₃): amino-methyl δ 7.73 (s, 1H), 7.63–7.05 (m, 11H), 5.44 (s,2H), 3.69 (s, 2H), 2.06 (s, 6H). 183 phenyl diethyl-amino- MS (ES) 662.1(M+1), ¹H NMR (300 MHz, CDCl₃): methyl δ 7.84 (s, 1H), 7.72–7.22 (m,11H), 5.54 (s, 2H), 3.88 (s, 2H), 2.40 (q, J = 7.2 Hz, 4H), 0.78 (t, J =7.2 Hz, 6H. 184 phenyl pyrrolidin-1- MS (ES) 660.1 (M+1), ¹H NMR (300MHz, CDCl₃): yl-methyl δ 7.73 (s, 1H), 7.62–7.11 (m, 11H), 5.45 (s, 2H),3.88 (s, 2H), 2.36 (br s, 4H), 1.53 (br s, 4H). 185 phenyl 2-(diethyl-MS (ES) 676.2 (M+1), ¹H NMR (300 MHz, CDCl₃): amino)-ethyl δ 7.79 (s,1H), 7.47 (s, 2H), 7.74–6.96 (m, 9H), 5.43 (s, 2H), 3.93 (t, J = 8.1 Hz,2H), 3.47 (t, J = 7.1 Hz, 2H), 3.23 (qd, J = 7.2, 2.0 Hz, 4H), 1.19 (t,J = 7.2 Hz, 6H). 186 phenyl 2-(isopropyl- MS (ES) 662.2 (M+1), ¹H NMR(300 MHz, CDCl₃): amino)-ethyl δ 7.84 (s, 1H), 7.72 (dd, J = 7.5, 2.0Hz, 1H), 7.60– 7.14 (m, 10H), 5.45 (s, 2H), 3.17 (app t, 2H), 3.00 (m,1H), 2.79 (m, 2H), 1.14 (d, J = 6.6 Hz, 6H). 187 phenyl 2- MS (ES) 690.2(M+1), ¹H NMR (300 MHz, CDCl₃): (morpholino)- δ 7.84 (s, 1H), 7.73 (dd,J = 7.6, 1.7 Hz, 1H), 7.60– ethyl 7.16 (m, 10H), 5.44 (s, 2H), 3.62 (t,J = 4.5 Hz, 4H), 3.13 (t, J = 7.6 Hz, 2H), 2.79 (t, J = 7.6 Hz, 2H),2.50 (ap t, J = 4.5 Hz, 4H). 188 phenyl 2-(dimethyl- MS (ES) 648.1(M+1), ¹H NMR (300 MHz, CDCl₃): amino)-ethyl δ 7.80 (s, 1H), 7.45–6.85(m, 11H), 5.39 (s, 2H), 4.01 (t, J = 7.7 Hz, 2H), 3.62 (t, J = 7.7 Hz,2H), 3.14 (s, 6H). 189 phenyl 2-(pyrrolidin- MS (ES) 674.1 (M+1), ¹H NMR(300 MHz, CDCl₃): 1-yl)-ethyl δ 7.70 (s, 1H), 7.40–6.85 (m, 11H), 5.34(s, 2H), 3.82 (t, J = 7.6 Hz, 2H), 3.55 (t, J = 7.6 Hz, 2H), 3.30 (m,4H), 1.85 (m, 4H). 190 phenyl methylamino- MS/ES(M+1): 620.0; R_(f) =0.38 (10:1 CHCl₃/MeOH) methyl 191 phenyl ethylamino- MS/ES(M+1): 634.1;R_(f) = 0.39 (10:1 CHCl₃/MeOH) methyl 192 methyl pyrrolidin-1- LC/MS(ES) 598.0 (M+H). ¹H NMR (400 MHz, yl-methyl CHCl₃) δ 7.89 (s, 1H), 7.68(m, 1H), 7.61 (s, 2H), 7.35 (m, 2H), 7.28 (m, 1H), 5.57 (s, 2H), 3.96(s, 2H), 2.51 (s, 3H), 2.43 (m, 4H), 1.58 (m, 4H). 193 methylmorpholino- LC/MS (ES) 614.0 (M+H). ¹H NMR (400 MHz, methyl CHCl₃) δ7.89 (s, 1H), 7.68 (m, 1H), 7.61 (s, 2H), 7.35 (m, 2H), 7.28 (m, 1H),5.57 (s, 2H), 3.84 (s, 2H), 3.38 (s, 4H), 2.55 (s, 3H), 2.36 (m, 4H).194 morpholino morpholino- MS (ES+) 685.1 (M+1), MS (ES−) 683.1 (M−1).¹H methyl NMR (400 MHz, CDCl₃) δ 7.87 (s, 1H), 7.69 (s, 2H), 7.68 (m,1H), 7.34 (m, 2H), 7.24 (m, 1H), 5.50 (s, 2H), 3.85 (s, 2H), 3.74 (m,4H), 3.39 (m, 4H), 3.00 (m, 4H), 2.38 (m, 4H). 195 morpholinopyrrolidin-1- MS (ES+) 669.1 (M+1), MS (ES−) 667.1 (M−1). ¹H yl-methylNMR (400 MHz, CDCl₃) δ 7.86 (s, 1H), 7.72 (s, 2H), 7.65 (m, 1H), 7.33(m, 2H), 7.27 (m, 1H), 5.49 (s, 2H), 3.96 (s, 2H), 3.72 (m, 4H), 2.98(m, 4H), 2.44 (m, 4H), 1.65 (m, 4H). 196 morpholino dimethyl- MS (ES+)643.0 (M+1), MS (ES−) 641.1 (M−1). ¹H amino-methyl NMR (400 MHz, CDCl₃)δ 7.86 (s, 1H), 7.72 (s, 2H), 7.67 (m, 1H), 7.34 (m, 2H), 7.27 (m, 1H),5.49 (s, 2H), 3.72 (m, 6H), 2.98 (m, 4H), 2.06 (s, 6H). 197 pyridin-3-ylmorpholino- Exact Mass 676.5; MS (ESI) m/z 677.5 (M+1); ¹H methyl NMR(300 MHz, CDCl₃) δ 2.41–2.43 (t, 4H, J = 4.62 Hz), 3.44–3.46 (t, 4H, J =4.44 Hz), 3.86 (s, 2H), 5.54 (s, 2H), 7.26–7.44 (m, 6H), 7.58 (dt, 1H),7.68–7.70 (m, 1H), 7.84 (s, 1H), 8.53 (d, 1H), 8.77–8.78 (dd, 1H). 198pyridin-4-yl morpholino- ¹H NMR (300 MHz, CDCl₃) δ 2.41 (br s, 4H), 3.49methyl (br s, 4H), 3.91 (br s, 2H), 5.48(s, 2H), 7.17 (d, J = 5.12 Hz,2H), 7.27 (m, 1H), 7.34–7.41 (m, 4H), 7.69 (d, J = 7.78 Hz, 1H), 7.85(s, 1H), 8.77 (m, 2H); MS (ESI) m/z 677.3(M+1).

Example 199[3-Aminomethyl-5-(2-chloro-phenyl)-isoxazol-4-yl]-[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H[1,2,3]triazol-4-yl]-methanone

Combine[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-3-hydroxymethyl-isoxazol-4-yl]-methanone(0.30 g, 0.49 mmol), diphenyl phosphoryl azide (0.13 mL, 0.59 mmol),1,8-diazabicyclo[5.4.0]undec-7-ene (0.09 mL, 0.59 mmole) in THF (2 mL)and stir at RT overnight. Filter off the solid and concentrate thefiltrate. Dissolve the crude product in THF (2 mL), addtriphenylphosphine (0.16 g, 0.59 mmole), and a few drops of water. Stirthe mixture overnight. Purify the resulting amine by sequentiallypassing through a short silica gel column (gradient elution with EtOAc,2% MeOH in EtOAc, 5% MeOH/2% NH₄OH(aq) in EtOAc), a SCX column (elutionwith 1:1 MeOH/CH₂Cl₂ and then 3.5 M NH₃ in MeOH) and again a shortsilica gel column (gradient elution with EtOAc, 5% MeOH/2% NH₄OH (aq) inEtOAc) to provide a yellow oil (0.14 g, 47%). ¹H NMR (400 MHz, CDCl₃) δ4.07 (s, 2H), 5.45 (s, 2H), 7.18–7.25 (m, 3H), 7.30–7.40 (m, 3H), 7.44(t, J=7.42 Hz, 1H), 7.74 (d, J=7.62 Hz, 1H), 7.87 (s, 1H), 8.81 (m, 2H);MS (ESI) m/z 607.1 (M+1).

General Example K

To a solution of the appropriate alkyne (1 eq.) in toluene (0.25 M), addthe azide of interest (2 eq.). Heat this reaction at 120° C. for 18 h.in a sealed tube. Concentrate the solution and purify the residue bychromatography on silica gel to yield title compound.

By the method of General Example K, the following compounds may beprepared and isolated.

Ex. # R^(a) R⁵ Physical Data 200 3,5-dichloro isopropyl R_(f) = 0.12(2:1 Hex/EtOAc). MS (ES) 505.0 (M+1) 201 3,5-dimethyl isopropylR_(f)=0.19 (2:1 Hex/EtOAc). MS (ES) 465.1 (M+1) 202 3,5-dichloro methylR_(f) = 0.11 (2:1 Hex/EtOAc). MS (ES) 477.0 (M+1) 203 3,5-dimethylmethyl R_(f) = 0.14 (2:1 Hex/EtOAc). MS (ES) 437.1 (M+1) 204 3-fluoro-5-methyl R_(f) = 0.11 (2:1 Hex/EtOAc). MS (ES) 495.0 (M+1) trifluromethyl205 3,5-bis- isopropyl R_(f) = 0.53 (2:1 Hex/EtOAc). MS (ES) 573.0 (M+1)trifluoromethyl 206 3-fluoro-5- isopropyl R_(f) = 0.11 2:1 Hex/EtOAc. MS(ES) 523.0 (M+1) trifluoromethyl 207 2-fluoro-5- isopropyl R_(f) = 0.182:1 Hex/EtOAc. MS (ES) 523.0 (M+1) trifluoromethyl 208 4-fluoro-3-isopropyl R_(f) = 0.08 2:1 Hex/EtOAc. MS (ES) 523.0 (M+1)trifluoromethyl 209 3,5-dimethyl methyl R_(f) = 0.14 2:1 Hex/EtOAc. MS(ES) 437.1 (M+1)

Example 210[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-2-yl-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-3-hydroxymethyl-isoxazol-4-yl]-methanone

Dissolve1-[5-(2-chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-4-yl]-3-pyridin-2-yl-propynone(0.27 g, 0.64 mmol) in toluene (10.0 mL), add1-azidomethyl-3,5-bis-trifluoromethyl-benzene (0.26 g, 0.95 mmol) andheat to 100° C. After 18 h., concentrate the reaction mixture and purifycrude material by flash chromatography using a linear gradient of 15% to40% EtOAc in hexanes to give[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-2-yl-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-3-cyclohexyloxymethyl-isoxazol-4-yl]-methanone.Dissolve this material in methanol (15.0 mL), add p-toluenesulfonic acidmonohydrate (0.09 g, 0.48 mmol) and stir at RT for 3 h.

Dilute reaction mixture with 1N NaOH and extract with EtOAc. Wash theorganic layer with water and brine, then dry, filter, and concentrate.Purify the residue by flash chromatography using a linear gradient of50% to 70% EtOAc in hexanes to give the title compound (0.11 g, 46%). MS[ES] 607.1 (M)⁺. ¹H NMR (400 MHz, CHCl₃) δ 8.79 (d, 1H, J=4.1 Hz), 7.88(m, 2H), 7.81 (s, 1H), 7.67 (dd, 1H, J=7.9, 1.6 Hz), 7.62 (s, 2H), 7.47(m, 1H), 7.39 (t, 1H, J=7.4 Hz), 7.30 (dt, 1H, J=7.4, 1.8 Hz), 7.17 (d,1H, J=7.9 Hz), 5.87 (s, 2H), 4.87 (s, 2H), 3.92 (br s, 1H).

Example 211[3-(2-chloro-phenyl)-5-(1-hydroxy-1-methyl-ethyl)-isoxazol-4-yl]-[1-(3-fluoro-5-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-methanone

In a 10 mL screwcap test tube, dissolve1-[3-(2-chloro-phenyl)-5-(1-methyl-1-trimethylsilanyloxy-ethyl)-isoxazol-4-yl]-3-pyridin-3-yl-propynone(60 mg, 0.137 mmol) in toluene (1 mL) and add1-azidomethyl-3-fluoro-5-trifluoromethyl-benzene (60 mg, 0.273 mmol, 2eq.). Seal the test tube and warm to 120° C. in block heater. After 24h., cool to RT, and add TBAF (0.25 mL of a 1M soln. in THF, 0.25 mmol,1.8 eq.). After 1 h., concentrate the mixture and purify the residue bychromatography (silica gel, hexanes/EtOAc 3:1 to 1:2 gradient) toprovide 26 mg (33%) of the title compound as a solid. m.p. 180° C.; TLC:R_(f)=0.38 (1:2 hexanes/EtOAc); MS(ES) 586.1 (M+1), 568.1 [(M−OH)+].

Example 212[3-(2-chloro-phenyl)-5-(1-hydroxy-1-methyl-ethyl)-isoxazol-4-yl]-{5-pyridin-3-yl-1-[1-(3-trifluoromethyl-phenyl)-ethyl]-1H-[1,2,3]triazol-4-yl}-methanone

By a method similar to Example 211, using the appropriate startingmaterials, the title compound may be prepared and isolated. TLC:R_(f)=0.27 (1:2 hexanes/EtOAc); MS(ES) 582.1 (M+1), 564.1 [(M−OH)⁺].

The following compounds may be prepared and isolated using a methodanalogous to Example 211.

Ex. # R^(a) Physical Data 213 3,5-dichloro m.p. 187° C.; TLC: R_(f) =0.35 (1:2 hexanes/EtOAc); MS(ES) 568.1 (M+1), 550.0 [(M—OH)⁺] 2143,5-dimethyl TLC: R_(f) = 0.52 (1:2 hexanes/EtOAc); MS(ES) 528.2 (M+1),510.2 [(M—OH)⁺] 215 2-methoxy-5- TLC: R_(f) = 0.23 (1:2 hexanes/EtOAc);MS(ES) 614.1 (M+1), trifluoro- 596.1 [(M—OH)⁺] methoxy 216 3-trifluoro-m.p. 161° C.; TLC: R_(f) = 0.24 (1:2 hexanes/EtOAc); MS(ES) methyl 568.1(M+1), 550.1 [(M—OH)⁺] 217 3,5-difluoro m.p. 136° C.; TLC: R_(f) =0.40(1:2 hexanes/EtOAc); MS(ES) 536.1 (M+1), 518.1 [(M—OH)⁺] 2183-trifluoro- m.p. 133° C.; TLC: R_(f) = 0.37 (1:2 hexanes/EtOAc); MS(ES)methoxy 584.1 (M+1), 566.1 [M—OH)⁺] 219 2-fluoro-5- TLC: R_(f) = 0.44(1:2 hexanes/EtOAc); MS(ES) 586.1 (M+1), trifluoro- 568.1 [(M—OH)⁺]methyl

By a method analogous to Example 211, the following compounds may beprepared and isolated.

Ex. # R^(a) Physical Data 220 3-fluoro-5- MS (ES) 557.0 (M⁺+1); TLCR_(f) = 0.1 (50% EtOAc in trifluoromethyl hexanes). 221 2-fluoro-5- MS(ES) 557.0 (M⁺+1); TLC R_(f) = 0.1 (50% EtOAc in trifluoromethylhexanes). 222 4-fluoro-3- MS (ES) 557.0 (M⁺+1); TLC R_(f) = 0.1 (50%EtOAc in trifluoromethyl hexanes). 223 3-trifluoro- MS (ES) 555.8(M⁺+1); TLC R_(f) = 0.1 (50% EtOAc in methoxy hexanes). 224 3,4-difluoroMS (ES) 508.1, 510.1 (M⁺+1); TLC R_(f) = 0.11 (50% EtOAc/CH₂Cl₂)

General Example L

Add (diethylamino)sulfur trifluoride (1 eq.) to a solution of thealcohol of interest (1 eq.) in dichloromethane (0.05 M) at −78° C. Stirat −78° C. for 10 min., warm to RT for 30 min. to 3 h. Treat reactionmixture with water and extract with dichloromethane. Wash the organicphase with brine then dry over MgSO₄, filter, and concentrate. Purifythe residue by flash chromatography using a linear gradient of 50% to70% EtOAc in hexane to give the title compound.

By the method of General Example L, the following compounds may beprepared and isolated.

Ex. # R⁵ Physical Data 225 4-isopropyl- MS (ES) 659.2 (M+H); ¹H NMR (400MHz, CHCl₃) δ 7.87 piperazin-1-yl (s, 1H), 7.69 (dd, 1H, J = 7.8, 1.4Hz), 7.65 (s, 2H), 7.30–7.40 (m, 2H), 7.21 (dd, 1H, J = 7.8, 1.0 Hz),5.71 (d, 2H, J = 46.5 Hz), 5.45 (s, 2H), 3.04 (m, 4H), 2.73 (s, 1H, J =6.5 Hz), 2.54 (m, 4H), 1.03 (d, 6H, J = 6.5 Hz). 226 pyridin-3-yl MS(ES) 610.1 (M+H). 227 pyridin-4-yl MS (ES) 610.1 (M+H).

General Example M

Add [bis(2-methoxyethyl)amino]sulfur trifluoride (2.5 eq.) to a solutionof the appropriate carbaldehyde (1 eq.) in dichloromethane (0.1 M) andstir at RT for 4 h. Dilute with water and extract with EtOAc (2×).Combine the EtOAc extracts and wash with brine, then dry over MgSO₄,filter, and concentrate. Purify the residue by flash chromatographyusing a linear gradient of 60% to 90% EtOAc in hexane to give theproduct.

By the method of General Example M, the following compounds may beprepared and isolated.

Ex. # R⁵ Physical Data 228 pyridin-4-yl MS (ES+) 628.1 (M+H); ¹H NMR(400 MHz, CHCl₃) δ 8.80 (br s, 2H), 7.87 (s, 1H), 7.74 (dd, 1H, J = 7.5,2.0 Hz), 7.44 (m, 2H), 7.39 (s, 2H), 7.27 (dd, 1H, J = 7.8, 1.5 Hz),7.19 (m, 2H), 7.08 (t, 1H, J = 53.3 Hz) 5.49 (s, 2H). 229 pyridin-3-ylMS [ES] 628.0 (M+H)⁺; ¹H NMR (400 MHz, CHCl₃) δ 8.78 (d, 1H, J = 3.4Hz), 8.50 (s, 1H), 7.84 (s, 1H), 7.73 (dd, 1H, J = 6.9, 2.4 Hz), 7.73(dd, 1H, J = 6.9, 2.4 Hz), 7.60 (dt, 1H, J = 8.4, 2.4 Hz), 7.39–7.47 (m,3H), 7.35 (s, 2H), 7.29 (dd, 1H, J = 7.5, 2.4Hz), 7.08 (t, 1H, J = 53.3Hz), 5.51 (s, 2H).

Example 230[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-[4-(2-chloro-phenyl)-2H-pyrazol-3-yl]-methanone

Dissolve1-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-3-(2-chloro-phenyl)-propynone(48 mg, 0.090 mmol) in THF/ether (1.0 mL of 50/50 mix) and addtrimethylsilyl diazomethane (50.0 μL of a 2.0 molar solution in hexanes,0.099 mmol). Stir the mixture at RT in a sealed tube. After 48 h.,concentrate and purify by chromatography (silica gel, hexanes/EtOAcgradient) to provide 25.0 mg of a clear colorless liquid. Exact Mass575.1: MS (aspci): m/z=576.0 (M+1), 574.0 (M−1); ¹H NMR (250 MHz,Pyridine doped CDCl₃) δ 8.97 (s, 0.5H), 7.69 (s, 1H), 7.40–7.00 (m,12.5H), 5.46 (s, 2H).

By a method similar to Example 230, the following compounds may beprepared and isolated.

Ex. # R⁵ Physical Data 231 pyridin-3-yl Exact Mass 576.09; MS (ESI) m/z575.2 (M−1). ¹H NMR (300 MHz, CDCl₃) δ 5.62 (s, 2H), 7.21–7.27 (m, 2H),7.30–7.33 (m, 1H), 7.36–7.41 (m, 2H), 7.47 (s, 2H), 7.52–7.54 (m, 1H),7.69 (s, 1H), 7.84 (s, 1H), 8.5 (d, 1H, J = 1.36 Hz), 8.72 (dd, 1H, J =4.80, 1.67 Hz). 232 pyridin-4-yl MS (ES) 577.1, 579.1 (M⁺+1). R_(f) =0.13 (66.6% EtOAc/Hex) 233 methyl MS [ES] 514.1 (M+H)⁺, 512.1 (M−H)⁻. ¹HNMR (400 MHz, CHCl₃) δ 13.35 (br s, 1H), 7.90 (s, 1H), 7.70 (br s, 3H),7.48 (m, 1H), 7.38 (m, 1H), 7.30–7.33 (m, 2H), 5.69 (s, 2H), 2.58 (s,3H).

By a method similar to Example 230, the following compounds may beprepared.

Ex. # R⁵ R⁷ Physical Data 234 pyridin-3-yl hydrogen Exact Mass 575.1; MS(aspci): m/z = 576.1 (M+1), 574.1 (M−1); ¹H NMR (500 MHz, CDCl₃) δ 9.54(s, 1H), 8.89 (d, J = 1.7 Hz, 1H), 8.68 (dd, J = 4.8, 1.7 Hz, 1H), 8.05(s, 1H), 7.91 (s, 2H), 7.84 (m, 1H), 7.70 (dd, J = 8.3, 3.0 Hz, 1H),7.40 (d, J = 8.3 Hz, 1H), 7.27–7.20(m, 2H), 6.02 (s, 2H). 235 phenylethoxy- Exact Mass 648.1: MS (aspci): m/z = 648.1 (M+1), carbonyl 646.0(M−1); ¹H NMR (250 MHz, CDCl₃) δ 7.82 (s, 1H), 7.55–7.38 (m, 5H),7.35–7.15 (m, 6H), 5.58 (s, 2H), 4.25 (q, J = 6.2 Hz, 2H), 1.13 (t, J =6.3 Hz, 3H). 236 pyridin-4-yl hydrogen MS (ES) 577.1, 579.1 (M⁺+1).R_(f) = 0.23 (66.6% EtOAc/Hex) 237 methyl hydrogen MS [ES] 514.1 (M+H)⁺,512.1 (M—H)⁻. ¹H NMR (400 MHz, CHCl₃) δ 11.86 (br s, 1H), 8.98 (s, 1H),7.88 (s, 1H), 7.68 (s, 2H), 7.44–7.48 (m, 2H), 7.32–7.40 (m, 2H), 5.62(s, 2H), 2.52 (s, 3H).

General Example N

Dissolve the pyrazole of interest in THF (10 mL) and cool in an ice bathunder N₂. Add BuLi (1.6 M in hexanes, 0.50 mL) and stir for 1 h., thenadd iodomethane and all the mixture to stir overnight while warming toRT. Quench the reaction with water and extract with EtOAc. Dry thecombined extracts over Na₂SO₄, filter, and concentrate in vacuo. Purifythe residue by chromatography over silica gel (Hex/EtOAc gradient).

By the method of General Example N, the following compounds may beprepared and isolated.

Ex. # R⁵ Physical Data 238 pyridin-4-yl MS (ES) 591.1, 593.1 (M⁺+1).R_(f) = 0.06(66.6% EtOAc/Hex) 239 pyridin-3-yl MS (ES) 591.1, 593.2(M⁺+1). R_(f) = 0.06(66.6% EtOAc/Hex) 240 methyl LC/MS [ES] 528.0(M+H)⁺; ¹H NMR (400 MHz, CHCl₃) δ 7.88 (s, 1H), 7.70 (s, 2H), 7.53 (s,1H), 7.33–7.40 (m, 2H), 7.21–7.25 (m, 2H), 5.60 (s, 2H), 4.10 (s, 3H),2.50 (s, 3H). 241 dimethyl- MS [ES] 556.9 (M+1)⁺; ¹H NMR (400 MHz,CHCl₃) δ 7.86 (s, 1H), amino 7.81 (s, 2H), 7.52 (s, 1H), 7.33–7.36 (m,2H), 7.16–7.24 (m, 2H), 5.50 (s, 2H), 4.01 (s, 3H), 2.71 (s, 6H). 242morpholino MS [ES] 599.1 (M+H)⁺; ¹H NMR (400 MHz, CHCl₃) δ 7.87 (s, 1H),7.83 (s, 2H), 7.52 (s, 1H), 7.33–7.36 (m, 2H), 7.18–7.25 (m, 2H), 5.53(s, 2H), 4.01 (s, 3H), 3.72 (m, 4H), 2.99 (m, 4H). 243 thio- MS [ES]647.0 (M+H)⁺; ¹H NMR (400 MHz, CHCl₃) δ 7.91 (s, 1H), morpholine- 7.63(s, 2H), 7.55 (s, 1H), 7.40 (m, 1H), 7.20 (m, 1H), 7.04 (m, 2H),1,1-dioxide 5.42 (s, 2H), 4.16 (s, 3H), 3.57 (m, 4H), 3.17 (m, 4H).

By the method of General Example N, the following compounds may beprepared.

Ex. # R⁵ Physical Data 244 methyl MS-[ES] 528.0, (M+H)⁺. ¹H NMR (400MHz, CHCl₃) δ 7.90 (s, 1H), 7.58 (s, 1H), 7.56 (s, 2H), 7.35 (dd, 1H, J= 7.6, 1.5 Hz), 7.15 (dt, 1H, J = 6.9, 2.0 Hz), 7.00–7.09 (m, 2H), 5.46(s, 2H), 4.15 (s, 3H), 2.52 (s, 3H). 245 dimethyl- MS [ES] 556.9 (M)⁺.¹H NMR (400 MHz, CHCl₃) δ 7.87 (s, amino 1H), 7.63 (s, 2H), 7.55 (s,1H), 7.29 (dd, 1H, J = 7.2, 1.5 Hz), 7.10 (dd, 1H, J = 7.2, 1.5 Hz),7.05 (dd, 1H, J = 7.9, 1.5 Hz), 6.95 (dt, 1H, J = 7.9, 1.5 Hz), 5.37 (s,2H), 4.15 (s, 3H), 2.78 (s, 6H). 246 morpholino MS [ES] 599.1 (M+H). ¹HNMR (400 MHz, CHCl₃) δ 7.89 (s, 1H), 7.60 (s, 2H), 7.55 (s, 1H), 7.30(dd, 1H, J = 7.8, 1.8 Hz), 7.10 (dt, 1H, J = 7.4, 1.4 Hz), 7.02 (dd, 1H,J = 7.8, 1.4 Hz), 6.96 (dt, 1H, J = 7.4, 1.4 Hz), 5.39 (s, 2H), 4.16 (s,3H), 3.76 (m, 4H), 3.04 (m, 4H). 247 thio- MS [ES] 647.0 (M+H)⁺. ¹H NMR(400 MHz, CHCl₃) δ 7.91 morpholine- (s, 1H), 7.63 (s, 2H), 7.55 (s, 1H),7.40 (m, 1H), 7.20 (m, 1H), 1,1-dioxide 7.04 (m, 2H), 5.42 (s, 2H), 4.16(s, 3H), 3.57 (m, 4H), 3.17 (m, 4H).

Example 248[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-1-methyl-1H-pyrazol-4-yl]-methanone

Using the method of General Example N, the title compound may beprepared and isolated. MS (ES)591.1, 593.1 (M⁺+1). R_(f)=0.30 (66.6%EtOAc/Hex).

Example 249[1-(3,5-bis-trifluoromethyl-benzyl)-5-methyl-1H-[1,2,3]triazol-4-yl]-[3-(2-chloro-phenyl)-1-methyl-1H-pyrazol-4-yl]-methanone

Using the method of General Example N, the title compound may beprepared and isolated. MS [ES] 528.1 (M+H)⁺, 526.1 (M−H)⁻. ¹H NMR (400MHz, CHCl₃) δ 8.98 (s, 1H), 7.87 (s, 1H), 7.68 (s, 2H), 7.45 (m, 2H),7.40 (m, 2H), 5.61 (s, 2H), 4.04 (s, 3H), 2.49 (s, 3H).

Example 250[1-(3,5-Bis-trifluoromethyl-benzyl)-5-methyl-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-1-methyl-1H-pyrazol-4-yl]-methanone

Using the method of General Example N, the title compound may beprepared and isolated. MS [ES] 528.1 (M+H)⁺, 526.1 (M−H)⁻; ¹H NMR (400MHz, CHCl₃) δ 8.91 (s, 1H), 7.87 (s, 1H), 7.67 (s, 2H), 7.53 (dd, 1H,J=8.3, 1.5 Hz), 7.32–7.55 (m, 3H), 5.62 (s, 2H), 3.69 (s, 3H), 2.49 (s,3H).

Example 251

[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-[1-(2-chloro-phenyl)-1H-imidazol-2-yl]-methanone

Add BuLi (0.80 mL, 1.28 mmol) to a −78° C. solution of1-(2-chloro-phenyl)-1H-imidazole (200 mg, 1.12 mmol) in THF (3 mL). Stirat −78° C. for 20 min., then add a solution of1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazole-4-carboxylicacid methoxy-methyl-amide (261 mg, 0.57 mmol) in THF (2 mL) via cannula.Stir the resulting solution at −78° C. for 10 min., then allow to warmto RT and stir for 2 h. Add 1N HCl (1.3 mL) and stir for 30 min. Dilutereaction with EtOAc (50 mL) and wash with water (20 mL), saturatedNaHCO₃ (20 mL) and brine (20 mL). Dry, filter and concentrate theorganic solution and purify the crude material by silica gelchromatography (20% to 80% EtOAc/hexanes) to give a brown solid.Trituration with cold ether gives the title compound as a fine whitepowder. MS [ES] 577.2 (M+H)+. ¹H NMR (400 MHz, CHCl₃) δ 8.68 (dd, 1H,J=1.4, 4.8 Hz), 8.48 (d, 1H, J=1.8 Hz), 7.81 (s, 1H), 7.48 (m, 3H), 7.46(m, 1H), 7.44 (m, 1H), 7.34 (m, 4H), 7.17 (m, 1H), 5.60 (s, 2H).

General Example O

Add Mg turnings (1.2 eq.) and a small crystal of iodine to a solution of5-bromo-oxazole (1 eq.) in freshly distilled THF (0.2 M). Stir themixture at reflux for 1.5 h., then cool to RT. Add via cannula asolution of the appropriate methoxy-methyl-amide (0.8 eq.) in THF (0.2M). Stir the solution at reflux for 30 min., then cool to RT and stirfor 1 h. Dilute solution with water, neutralize with 1N HCl, and extractwith EtOAc. Combine the organic layers and wash with saturated aqueousNaHCO₃ and brine, then dry, filter, and concentrate. Purify the crudematerial by flash chromatography.

By the method of General Example O, the following compounds may beprepared and isolated.

Ex. # R⁵ R⁷ Physical Data 252 pyridin-3-yl methyl MS (ES+) 592.0 (M+1),MS (ES−) 590.1 (M−1). ¹H NMR (400 MHz, CDCl₃) δ 8.73 (dd, 1H, J = 1.5,4.9 Hz), 8.50 (d, 1H, J = 2.1 Hz), 7.82 (s, 1H), 7.58 (dt, 1H, J = 1.7,7.8 Hz), 7.53 (dd, 1H, J = 2.0, 6.8 Hz), 7.41 (s, 2H), 7.37 (dd, 1H, J =5.0, 7.9 Hz), 7.31 (dt, 1H, J = 2.4, 6.8 Hz), 7.26 (m, 2H), 5.52,(s,2H), 2.63 (s, 3H). 253 pyridin-3-yl isopropyl MS (ES+) 620.1 (M+1), MS(ES−) 618.2 (M−1). ¹H NMR (400 MHz, CDCl₃) δ 8.73 (m, 1H), 8.51 (m, 1H),7.82 (s, 1H), 7.60 (m, 1H), 7.57 (m, 1H), 7.40 (s, 2H), 7.37 (dd, 1H, J= 4.9, 7.8 Hz), 7.32 (dt, 1H, J = 2.0, 7.3 Hz), 7.24 (m, 2H), 3.23(septet, 1H, J = 6.8 Hz), 1.44 (d, 6H, J = 6.8 Hz). 254 pyridin-3-ylcyclo- MS (ES+) 618.1 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ propyl 8.73 (dd,1H, J = 4.9, 1.5 Hz), 8.50(d, 1H, J = 2.1 Hz), 7.82 (s, 1H), 7.60 (dt,1H, J = 1.7, 7.8 Hz), 7.53 (dd, 1H, J = 7.8, 2.0Hz), 7.41 (s, 2H), 7.37(dd, 1H, J = 7.9, 5.0 Hz), 7.22–7.33 (m, 3H), 5.52 (s, 2H), 2.22 (m,1H), 1.18– 1.32 (m, 4H). 255 pyridin-4-yl cyclo- MS (ES+) 618.1 (M+H)⁺;¹H NMR (400 MHz, CDCl₃) δ propyl 8.71 (d, 2H, J = 6.0Hz), 7.83 (s, 1H),7.50 (dd, 1H, J = 7.8, 1.9 Hz), 7.43 (s, 2H), 7.18–7.30 (m, 3H), 7.16(m, 2H), 5.48 (s, 2H), 2.20 (m, 1H), 1.17–1.31 (m, 4H).

General Example P

Add MnO₂ (5–10 eq.) to a solution of the appropriate alcohol (1 eq.) inCH₂Cl₂ or toluene (˜0.1 M) and stir the mixture at RT. (The reaction maybe heated if necessary.) When the reaction is complete, filter themixture through Celite® and concentrate the filtrate. Purify the crudematerial by flash chromatography on silica gel.

Using the method of General Example P, the following compounds may beprepared and isolated.

Ex. # R⁵ R⁷ Physical Data 256 pyridin-4-yl methyl ¹H NMR (400 MHz,CDCl₃) δ 8.73 (s, 2H), 7.84 (s, 1H), 7.52 (dd, 1H, J = 1.9, 7.8 Hz),7.44 (s, 2H), 7.37 (dd, 1H, J = 5.0, 7.9 Hz), 7.30 (dt, 1H, J = 2.0, 6.9Hz), 7.27 (dd, 1H, J = 1.5, 7.4 Hz), 7.23 (m, 2H), 5.49 (s, 2H), 2.62(s, 3H). 257 chloro iso- MS (ES+) 577.0 (M+1)⁺. ¹H NMR (400 MHz, CDCl₃)δ propyl 7.90 (s, 1H), 7.76 (s, 2H), 7.54 (d, 1H, J = 7.3 Hz), 7.27 (m,3H), 5.60 (s, 2H), 3.28 (septet, 1H, J = 6.8 Hz), 1.47 (d, 6H, J = 6.8Hz). 258 chloro cyclo- MS (ES+) 575.1 (M+H). ¹H NMR (400 MHz, CDCl₃) δpropyl 7.91 (s, 1H), 7.76 (s, 2H), 7.50 (m, 1H), 7.24-7.31 (m, 3H), 5.61(s, 2H), 2.60 (m, 1H), 1.33 (m, 2H), 1.23 (m, 2H). 259 chloro methyl MS(ES+) 549.0 (M+1)+. ¹H NMR (400 MHz, CDCl₃) δ 7.92 (s, 1H), 7.77 (s,2H), 7.52 (dd, IH, J = 1.9, 5.8 Hz), 7.28 (m, 3H), 5.62 (s, 2H), 2.68(s, 3H).

Example 260[5-Amino-3-(2-chloro-phenyl)-pyridazin-4-yl]-[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-methanone

To3-[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-4-(2-chloro-phenyl)-isoxazolo[3,4-d]pyridazine(100 mg, 0.166 mmol), add 8.0 ml of acetonitrile, and 170 μL of water,followed by molybdenum hexacarbonyl (22 mg, 0.083 mmol). Heat themixture to 80° C. for 4 h., then cool to RT. Pour the mixture through aplug of Celite® (1 cm) and silica gel (2 cm). Concentrate and purify theresidue by chromatography (silica gel, hexanes/EtOAc gradient) toprovide 42 mg of a yellow solid. Exact Mass 603.1: MS (aspci): m/z=603.9(M+1), m/z=601.9 (M−1); ¹H NMR (300 MHz, CDCl₃) δ 8.65–8.80 (m, 3H),7.79 (s, 1H), 7.65 (br d, J=7.4 Hz, 1H), 7.31 (s, 2H), 7.15–7.00 (m,2H), 6.96 (d, J=7.4 Hz, 1H), 6.87 (br t, J=7.4 Hz, 1H), 6.12 (br s, 2H),5.21 (ABq, J=22.5, 7.5 Hz, 2H).

Example 261[5-amino-3-(2-chloro-phenyl)-pyridazin-4-yl]-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-methanone

By the method of Example 260, using the appropriate starting materials,the title compound may be prepared and isolated. Exact Mass 602.9: MS(aspci): m/z=602.9 (M+1), m/z=601.0 (M−1); ¹H NMR (300 MHz, CDCl₃) δ8.68 (s, 1H), 7.62 (s, 1H), 7.61 (m, 1H), 7.43 (d, J=7.8 Hz, 1H),7.19–7.40 (m, 3H), 7.09 (s, 2H), 6.88–6.97 (m, 2H), 6.83 (m, 1H), 6.71(m, 1H), 6.11 (br s, ˜1H), 5.02–5.19 (m, 2H).

Using a method analogous to Example 260, the following compounds may beprepared and isolated.

Ex. # R⁵ Physical Data 262 pyridin-4-yl Exact Mass 602.9; MS (aspci):m/z = 602.9 (M+1), m/z = 600.1 (M−1); ¹H NMR (300 MHz, CDCl₃) δ 8.71 (brs, 2H), 8.22 (d, J = 7.1 Hz, 1H), 7.80 (s, 1H), 7.38 (dd, J = 7.2, 0.6Hz, 1H), 7.32 (s, 2H), 7.04 (d, J = 6.0 Hz, 2H), 6.91–7.00 (m, 2H), 6.78(m, 1H), 6.54 (d, J = 6.0, Hz, 2H), 5.67 (s, 2H), 5.24 (ABq, J = 21.6,10.5 Hz, 2H). 263 phenyl Exact Mass 601.1: MS (aspci): m/z = 601.9(M+1); ¹H NMR (300 MHz, CDCl₃) δ 8.22 (d, J = 3.2 Hz, 1H), 7.75 (s, 1H),7.51–7.34 (m, 4H), 7.27 (s, 2H), 7.10–6.90 (m, 4H), 6.76 (dt, J = 0.5,7.5 Hz, 1H), 6.55 d, J = 2.8 Hz, 1H, 5.61 s, 2H, 5.23 app d, J = 7.8 Hz,2H).

Example 264[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-(2′-chloro-biphenyl-2-yl)-methanone

Dissolve1-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-3-(2-chloro-phenyl)-propynone(100 mg, 0.188 mmol) in chlorobenzene (1 mL), add pyrone (19.8 mg, 16.6μL, 0.206 mmol) and heat the mixture at 130° C. After 24 h., add morepyrone (19.8 mg, 16.6 μL, 0.206 mmol). After another 24 h., cool to RTand concentrate. Purify by silica gel chromatography (hexanes/EtOAcgradient) to provide 88 mg of a clear colorless liquid. Exact Mass585.9: MS (aspci): m/z=586.1 (M+1); ¹H NMR (300 MHz, CDCl₃) δ 7.77–7.66(m, 3H), 7.25–7.6 (m, 6H), 7.30 (s, 2H), 7.05–7.20 (m, 2H), 7.05–6.90(m, 3H), 5.31 (s, 2H).

Example 2651-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-3-(2-chloro-phenyl)-propenone

To1-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-3-(2-chloro-phenyl)-propynone(50 mg, 0.0094 mmol), add 15 ml of pyridine, followed by 5% palladium onbarium sulfate (6.2 mg); stir at RT for 3 h. at 60 psi of hydrogen. Pourthe mixture through a plug of Celite® (1 cm) and silica gel (2 cm).Concentrate the clear, colorless liquid to 1.0 mL with azeotropicremoval of the pyridine with heptane. Purify by radial chromatography(hexanes/EtOAc gradient) to provide the desired product as a clearcolorless liquid (25 mg). Exact Mass 535.9: MS (aspci): m/z=536.0 (M+1),534.0 (M−1); ¹H NMR (300 MHz, CDCl₃) δ 7.83(s, 1H), 7.64–7.40 (m, 2H),7.51 (s, 2H), 7.38 (m, 1H), 7.28 (s, 3H), 7.24–7.10 (m, 2H), 5.62 s,1H), 5.55 (d, J=3.0 Hz, 1H).

Example 2661-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-3-(2-fluoro-phenyl)-propenone

Using a similar procedure as Example 265, with the appropriate startingmaterials, the title compound may be prepared and isolated. Exact Mass519.45: MS (aspci): m/z=520.1 (M+1), 518.1 (M+1); ¹H NMR (300 MHz,CDCl₃) δ 7.74 (s, 1H), 7.58 (m, 1H), 7.55–7.35 (m, 2H), 7.40 (s, 2H),7.19 (s, 2H), 7.15 (m, 1H), 7.03 (appt, J=12.0 Hz, 2H), 5.51 (s, 2H).

Example 2671-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-3-(2-chlorophenyl)-propan-1-one

Dissolve1-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-3-(2-chloro-phenyl)-propynone(1.04 g, 1.949 mmol) in THF (36 mL), add Platinum (IV) oxide (260 mg,1.15 mmol) and stir at RT for 48 h. under 60 psi of hydrogen. Filterthrough a plug of Celite® (1 cm) and silica gel (2 cm). Concentrate thefiltrate and purify the residue by chromatography (silica gel,EtOAc/Hexanes gradient) to provide the desired product as a clearcolorless liquid (550 mg). Exact Mass 537.10: MS (aspci): m/z=540.0(M+1); ¹H NMR (300 MHz, CDCl₃) δ 8.32 (s, 1H), 7.60–7.44 (m, 2H), 7.47(s, 2H), 7.22–7.40 (m, 3H), 7.33–7.10 (m, 4H), 5.57 (s, 2H), 3.52 (t,J=8.1 Hz, 6H), 3.14 (t, J=8.1 Hz, 2H).

Example 2683-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-imidazol-1-yl-1H-[1,2,3]triazol-4-yl]-2-(2-chloro-benzoyl)-3-oxo-propionitrile

Add Dess-Martin periodinane (1.5 g, 3.54 mmol) to a solution of[1-(3,5-Bis-trifluoromethyl-benzyl)-5-imidazol-1-yl-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-3-hydroxymethyl-isoxazol-4-yl]-methanone(0.7 g, 1.17 mmol) in dichloromethane (10.0 mL). Stir at RT for 4 h,dilute with EtOAc and wash with 2N NaOH, water and brine, then dry,filter, and concentrate. Recyrstallize crude material fromdichloromethane to give the title compound. (0.10 g, 15%). MS [ES] 567.0(M+H)⁺, 565.0 (M−H); ¹H NMR (400 MHz, DMSO-d₆) δ 8.04 (s, 1H), 7.70 (s,2H), 7.69 (s, 1H), 7.25 (br s, 2H), 7.19 (m, 2H), 7.03 (s, 1H), 6.98 (m,1H), 5.68 (s, 2H).

Example 269[1-(3,5-bistrifluoromethylbenzyl)-5-imidazol-1-yl-1H-[1,2,3]triazol-4-yl]-[5-(2-chlorophenyl)-3-hydroxymethyl-isoxazol-4-yl]-methanone

Heat a solution of[1-(3,5-bistriflurormethylbenzyl)-5-chloro-1H-[1,2,3]triazol-4-yl]-[5-(2-chlorophenyl)-3-(tetrahydropyran-2-yloxymethyl)-isoxazol-4-yl]-methanone(25.0 g, 0.039 mol) and imidazole (10.5 g, 0.154 mol) in DMSO (180 mL)at 90° C. for 24 h. Cool the solution to RT, add to ice water (700 mL),stir for 15 min. and filter. Add methylene chloride (400 mL) to the wetcake and place in a separatory funnel. Separate the layers and extractthe aqueous with methylene chloride (200 mL). Back extract the combinedorganic layers with water (2×200 mL), dry (magnesium sulfate), filter,and concentrate to a foam. Add MeOH (250 mL) and p-toluenesulfonic acidmonohydrate (7.3 g, 0.039 mol) and stir at RT for 2 h. Remove MeOH undervacuum and add methylene chloride (250 mL), water (200 mL), andsaturated sodium bicarbonate (50 mL). Separate layers and extract theaqueous layer with methylene chloride (100 mL). Combine the organiclayers, back extract with water (200 mL), dry (magnesium sulfate), treatwith acid-washed carbon, filter through Celite®, and concentrate undervacuum to an oil. Add diethyl ether (100 mL), stir for 1 h., add heptane(100 mL) over 20 min., stir for 1 h., filter, and dry to give crudetitle compound. Recrystallize as follows: add diethyl ether (500 mL),methylene chloride (100 mL) and MeOH (100 mL), concentrate solution, addheptane (350 mL) over 30 min., stir for 2 h., filter, and dry to givethe title compound. m.p. 148.8° C.; MS [ES] 597.1 (M+H)⁺, 595.1 (M−H)⁻.¹H NMR (400 MHz, CHCl₃) δ 7.91 (s, 1H), 7.74 (dd, 1H, J=7.6, 1.6 Hz)7.70 (br s, 1H), 7.45–7.49 (m, 3H), 7.41 (dt, 1H, J=7.6, 2.0 Hz), 7.34(br s, 1H), 7.21 (dd, 1H, J=8.0, 1.2 Hz), 6.92 (br s, 1H), 5.42 (s, 2H),4.83 (m, 2H), 3.00 (br s, 1H).

Example 270[1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-(3-phenyl-3H-[1,2,3]triazol-4-yl)-methanone

To a solution of[1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-(3-phenyl-5-trimethylsilanyl-3H-[1,2,3]triazol-4-yl)-methanone(0.050 g, 0.08 mmol) in THF (2 mL) add t-butyl ammonium flouride (1 Msoln. in THF, 1.2 mL, 1.2 mmol) and acetic acid (120 μL, 2.0 mmol) andheat at 65° C. After 72 h., remove from heat, and quench with sat. aq.NH₄C₁ and H₂O. Extract with EtOAc, dry over MgSO₄, filter, and purify byflash chromatography (EtOAc/Hexane 0%–50%) to give the title compound.¹H NMR (300 MHz, CDCl₃) δ 8.88 (s, 1H), 7.75 (s, 1H), 7.57–7.29 (m,10H), 7.09 (m, 2H), 5.50 (s, 2H).

Example 2714-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carbonyl]-5-(2-chloro-phenyl)-isoxazole-3-carbaldehydeoxime

To a solution of4-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carbonyl]-5-(2-chloro-phenyl)-isoxazole-3-carbaldehyde(0.076 g, 0.13 mmol) in CH₂Cl₂ (2 mL) and MeOH (2 mL), add sodiumacetate trihydrate (0.034 g, 0.25 mmol) and hydroxylamine.HCl (0.018 g,0.25 mmol) and stir at RT. After 1 h., quench with 75% sat. aq. NH₄Cl (4mL), extract with ethyl acetate, and wash with brine. Dry over MgSO₄,filter and concentrate under vacuum. Purify by flash chromatography,(EtOAc/Hexane 10%–50%) to give the title compound. MS(ES) 620.1 (M+1),¹H NMR (300 MHz, CDCl₃) δ 8.34 (s, 1H), 7.83 (br s, 2H), 7.74–7.16 (m,9H), 5.50 (s, 2H).

The compounds of the present invention can be administered alone or inthe form of a pharmaceutical composition, that is, combined withpharmaceutically acceptable carriers, or excipients, the proportion andnature of which are determined by the solubility and chemical propertiesof the compound selected, the chosen route of administration, andstandard pharmaceutical practice. The compounds of the presentinvention, while effective themselves, may be formulated andadministered in the form of their pharmaceutically acceptable salts, forpurposes of stability, convenience of crystallization, increasedsolubility, and the like.

Thus, the present invention provides pharmaceutical compositionscomprising a compound of the Formula I and a pharmaceutically acceptablediluent.

The compounds of Formula I can be administered by a variety of routes.In effecting treatment of a patient afflicted with disorders describedherein, a compound of Formula I can be administered in any form or modethat makes the compound bioavailable in an effective amount, includingoral and parenteral routes. For example, compounds of Formula I can beadministered orally, by inhalation, or by the subcutaneous,intramuscular, intravenous, transdermal, intranasal, rectal, occular,topical, sublingual, buccal, or other routes. Oral administration isgenerally preferred for treatment of the neurological and psychiatricdisorders described herein.

One skilled in the art of preparing formulations can readily select theproper form and mode of administration depending upon the particularcharacteristics of the compound selected, the disorder or condition tobe treated, the stage of the disorder or condition, and other relevantcircumstances. (Remington's Pharmaceutical Sciences, 18th Edition, MackPublishing Co. (1990)).

The pharmaceutical compositions are prepared in a manner well known inthe pharmaceutical art. The carrier or excipient may be a solid,semi-solid, or liquid material that can serve as a vehicle or medium forthe active ingredient. Suitable carriers or excipients are well known inthe art. The pharmaceutical composition may be adapted for oral,inhalation, parenteral, or topical use and may be administered to thepatient in the form of tablets, capsules, aerosols, inhalants,suppositories, solutions, suspensions, or the like.

The compounds of the present invention may be administered orally, forexample, with an inert diluent or capsules or compressed into tablets.For the purpose of oral therapeutic administration, the compounds may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gums and thelike. These preparations should contain at least 4% of the compound ofthe present invention, the active ingredient, but may be varieddepending upon the particular form and may conveniently be between 4% toabout 70% of the weight of the unit. The amount of the compound presentin compositions is such that a suitable dosage will be obtained.Preferred compositions and preparations according to the presentinvention may be determined by a person skilled in the art.

The tablets, pills, capsules, troches, and the like may also contain oneor more of the following adjuvants: binders such as povidone,hydroxypropyl cellulose, microcrystalline cellulose, gum tragacanth orgelatin; excipients such as dicalcium phosphate, starch, or lactose;disintegrating agents such as alginic acid, Primogel, corn starch andthe like; lubricants such as talc, magnesium stearate or Sterotex;glidants such as colloidal silicon dioxide; and sweetening agents, suchas sucrose, aspartame, or saccharin, or a flavoring agent, such aspeppermint, methyl salicylate or orange flavoring, may be added. Whenthe dosage unit form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier such as polyethyleneglycol or a fatty oil. Other dosage unit forms may contain other variousmaterials that modify the physical form of the dosage unit, for example,coatings. Thus, tablets or pills may be coated with sugar, shellac, orother coating agents. A syrup may contain, in addition to the presentcompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors. Materials used in preparing these variouscompositions should be pharmaceutically pure and non-toxic in theamounts used.

For the purpose of parenteral therapeutic administration, the compoundsof the present invention may be incorporated into a solution orsuspension. These preparations typically contain at least 0.001% of acompound of the invention, but may be varied to be between 0.001 andabout 90% of the weight thereof. The amount of the compound of Formula Ipresent in such compositions is such that a suitable dosage will beobtained. The solutions or suspensions may also include one or more ofthe following adjuvants: sterile diluents, such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents, such as benzylalcohol or methyl paraben; antioxidants, such as ascorbic acid or sodiumbisulfite; chelating agents, such as ethylene diaminetetraacetic acid;buffers, such as acetates, citrates or phosphates; and agents for theadjustment of tonicity, such as sodium chloride or dextrose. Theparenteral preparation can be enclosed in ampoules, disposable syringesor multiple dose vials made of glass or plastic. Preferred compositionsand preparations are able to be determined by one skilled in the art.

The compounds of the present invention may also be administeredtopically, and when done so, the carrier may suitably comprise asolution, ointment, or gel base. The base, for example, may comprise oneor more of the following: petrolatum, lanolin, polyethylene glycols,bees wax, mineral oil, diluents such as water and alcohol, andemulsifiers, and stabilizers. Topical formulations may contain aconcentration of a compound of Formula I or its pharmaceutical salt fromabout 0.1 to about 10% w/v (weight per unit volume).

The compounds of Formula I are antagonists of NK-1 receptors.Furthermore, the compounds of Formula I selectively antagonize NK-1receptors relative to other tachykinin receptors. The antagonistactivity of NK-1 receptor antagonists may be determined by the methodsbelow.

NK-1 Receptor Binding Assay

The IM-9 cell line is a well-characterized and readily available humancell line. See e.g., Annals of the New York Academy of Science, 190:221–234 (1972); Nature (London), 251:443–444 (1974); Proceedings of theNational Academy of Sciences (USA), 71:84–88 (1974). These cells areroutinely cultured in RPMI 1640 supplemented with 50 μg/ml gentamicinsulfate and 10% fetal calf serum.

The IM-9 cells are homogenized from cell pellets for crude membranes.The membranes are isolated by homogenizing tissue samples in 30 ml w/vwith 50 mM Tris buffer (pH 7.4). After an initial spin at 900×g, thesupernatant is transferred to a clean centrifuge tube and the membranesisolated by centrifugation at 38,000×g.

Approximately 25 μg of membranes are incubated with 0.2 nM[¹²⁵]-substance P (NEN, Boston, Mass.) in a receptor binding assay. Theassay buffer contains 50 mM Tris, 3 mM MnCl₂, 0.02% bovine serumalbumin, 40 μg/ml bacitracin, 2 μg/ml chymostatin, 4 μg/ml leupeptin and40 μg/ml thiorphan (pH 7.4). Binding studies are conducted in a finalvolume of 200 μl containing various concentrations of test compounds.Non-specific binding is determined by incubating some tubes in thepresence of 1 μM substance P (Peninsula, Belmont, Calif.).

Binding is terminated 1 hour later by rapid filtration using a TOMTEC96-well cell harvester (TOMTEC, Orange, Conn.) through GF/A filters thathave been presoaked with 0.3% polyethyleneimine (Sigma, St Louis) for 1hour. The filters are washed with 5 ml of ice-cold 50 mM Tris buffer (pH7.4) and placed in a drying oven at 60° C. The dried filters are treatedwith MeltiLex A melt-on scintillator sheets (Wallac, Gaithersburg, Md.),and the radioactivity retained on the filters counted using the Wallac1205 Betaplate scintillation counter. The results are analyzed using aLog-Logit plot from a Microsoft Excel™ workbook and converted to Kivalues with the Cheng-Prusoff equation. Protein concentrations aremeasured using Coomassie® protein assay reagent (Pierce, Rockford,Ill.), with BSA for standards (Bradford, 1976).

Binding studies are carried out to evaluate the ability of compounds ofthe present invention to inhibit NK-1 receptor activation. Such studiesprovide in vitro data regarding the efficacy of the compounds of thepresent invention. Representative Examples of the compounds of Formula(I) were tested in the receptor binding assay described herein and weredemonstrated to have binding affinities (K_(i) values) of ≦100 nM.

Several preclinical laboratory animal models have been described for anumber of the disorders associated with an excess of tachykinins. Onesuch in vivo assay, described below, may be used to determine whetherNK-1 receptor antagonists are CNS-penetrant.

Gerbil Foot-Tapping

The gerbil foot-tapping assay is well recognized in the art. Forexample, see Rupniak et al., Eur. J. Pharmacol. (1997) 326: 201–209.

Male Gerbils (Mongolian), weighing between 20–40 gm (Harlan Labs,Indianapolis, Ind.) are used for the experiments. Animals are allowed toacclimate prior to any testing.

An NK-1 receptor agonist, such as GR73632 (δ-Aminovaleryl [Pro⁹,N-Me-Leu¹⁰]-Substance P(7–11)) (Peninsula Labs), is dissolved inacidified saline (1 ml acetic acid in 1 liter of 0.09% saline) to make a1 mg/ml solution (corrected for peptide content). The stock solution isfurther diluted to 10 μg/ml in saline (0.9% normal saline), aliquotedand kept frozen until use. The stock solution is further diluted to 3pmol/5 μl in saline for i.c.v. injections.

Test compounds are formulated in appropriate vehicle to a concentrationof 1 ml/100 gm body weight. Compounds are dosed by oral gavage (p.o.) orsubcutaneously (s.c.) or intraperitoneally (i.p.) at pre-determinedtimes prior to intracerebroventricular (i.c.v.) challenge of agonist.For i.c.v. administration, test compound is co-injected with agonist.

Free hand i.c.v. injection is performed by direct vertical insertion ofa cuffed 27-gauge needle with a Hamilton 50 μl syringe, to a depth of4.5 mm below bregma. Light anesthesia with isoflurane may be neededprior to the injection, but is not used routinely.

Following i.c.v. injection of agonist, animals are placed in a plexiglasobservation box, and hind foot tapping events are counted for 5 minutes.Data collection is computerized.

Data are analyzed by ANOVA followed by Dunnett's test using JMPstatistical program (IBM platform). Data are expressed as number ofevents/5 minutes.

The results of NK-1 receptor binding studies demonstrate the ability ofcompounds of the present invention to act as antagonists of NK-1receptors. It is recognized that the compounds of the present inventionwould be expected to inhibit the effects of NK-1 receptor activation.Thus, the compounds of the present invention are expected to be usefulin the treatment of various disorders associated with excesstachykinins, as described to be treated herein, and other disorders thatcan be treated by such antagonists, as are appreciated by those skilledin the art.

In one embodiment, the present invention provides methods of treatingdisorders selected from the group consisting of anxiety, depression,psychosis, schizophrenia and other psychotic disorders,neurodegenerative disorders (including senile dementia of theAlzheimer's type, Alzheimer's disease, AIDS-associated dementia, andDown's syndrome), seizure disorders (including generalized and partialseizures), demyelinating diseases (including multiple sclerosis andamyotrophic lateral sclerosis), neuropathological disorders (includingperipheral neuropathy, diabetic and chemotherapy-induced neuropathy, andpost-herpetic and other neuralgias), acute and chronic obstructiveairway diseases (including adult respiratory distress syndrome,bronchopneumonia, bronchospasm, chronic bronchitis, drivercough, andasthma), inflammatory diseases (including inflammatory bowel disease,psoriasis, fibrositis, osteoarthritis, and rheumatoid arthritis),disorders of the musculo-skeletal system (such as osteoporosis),allergies (including eczema and rhinitis), hypersensitivity disorders(such as poison ivy), ophthalmic diseases (such as conjunctivitis,vernal conjunctivitis, and the like), cutaneous diseases (includingcontact dermatitis), atopic dermatitis, urticaria, other eczematoiddermatites, addiction disorders (including alcoholism), stress-relatedsomatic disorders, reflex sympathetic dystrophy (such as shoulder/handsyndrome), dysthymic disorders, adverse immunological reactions (such asrejection of transplanted tissues), disorders related to immuneenhancement or suppression (such as systemic lupus erythematosis),gastrointestinal disorders, diseases associated with the neuronalcontrol of viscera (such as ulcerative colitis, Crohn's disease andirritable bowel syndrome); disorders of bladder function (such asbladder detrusor hyper-reflexia and incontinence), atherosclerosis,fibrosis and collagen diseases (such as scleroderma and eosinophilicfascioliasis), irritative symptoms of benign prostatic hypertrophy,disorders associated with blood pressure (such as hypertension),disorders of blood flow caused by vasodilation or vasospastic diseases(such as angina, migraine, and Reynaud's disease), emesis (includingchemotherapy-induced nausea and acute or delayed emesis), and pain ornociception (including that attributable to or associated with any ofthe foregoing conditions), comprising: administering to a patient inneed thereof an effective amount of a compound of Formula I or apharmaceutical composition thereof. That is, the present inventionprovides methods of treating disorders associated with an excess oftachykinins, comprising: administering to a patient in need thereof aneffective amount of a compound of Formula I or a pharmaceuticalcomposition thereof.

The present invention contemplates the various disorders described to betreated herein and others that can be treated by such antagonists, asappreciated by those skilled in the art.

The disorders associated with an excess of tachykinins are treated byadministering an effective amount of a compound or pharmaceuticalcomposition of Formula I. An effective amount can be readily determinedby the attending diagnostician; as one skilled in the art, by the use ofconventional techniques and by observing results obtained underanalogous circumstances. In determining an effective amount, the dose ofa compound of Formula I, a number of factors are considered by theattending diagnostician, including, but not limited to: the compound ofFormula I to be administered; the species of mammal—its size, age, andgeneral health; the specific disorder involved; the degree ofinvolvement or the severity of the disorder; the response of theindividual patient; the mode of administration; the bioavailabilitycharacteristics of the preparation administered; the dose regimenselected; the use of other concomitant medication; and other relevantcircumstances.

An effective amount of a compound of Formula I is expected to vary fromabout 0.001 milligram per kilogram of body weight per day (mg/kg/day) toabout 100 mg/kg/day. Preferred amounts may be readily determined by oneskilled in the art.

Of the disorders associated with an excess of tachykinins that aretreated according to the present invention, the treatment of depression,anxiety, inflammatory bowel disease, irritable bowel syndrome, andemesis (chemotherapy-induced nausea and acute or delayed emesis) areparticularly preferred.

Thus, in a preferred embodiment, the present invention provides a methodfor treating a depressive disorder, including major depressive disorder,comprising: administering to a patient in need thereof an effectiveamount of a compound of Formula I or a pharmaceutical compositionthereof.

In another preferred embodiment, the present invention provides a methodfor treating anxiety, including generalized anxiety disorder, panicdisorder, and obsessive-compulsive disorder, comprising: administeringto a patient in need thereof an effective amount of a compound ofFormula I or a pharmaceutical composition thereof.

Disorders of the central nervous system, including depressive andanxiety disorders, have been characterized in the Diagnostic andStatistical Manual of Mental Disorders (DSM-IV™) (1994, AmericanPsychiatric Association, Washington, D.C.). The DSM-IV™ provides cleardescriptions of diagnostic categories. The skilled artisan willrecognize that there are alternative nomenclatures, nosologies, andclassification systems for these disorders, and that these systems mayevolve with medical scientific progress. For instance, the ICHPPC-2(International Classification of Health Problems in Primary Care)(3^(rd) edition, 1983, Oxford University Press, Oxford) provides analternative classification system. Thus, the terms “depression,”“depressive disorders,” “anxiety,” and “anxiety disorders” are intendedto include like disorders that are described in other diagnosticsources.

According to the fourth edition of the DSM-IV™, major depressivedisorders are characterized by one or more major depressive episodes,which consist of a period of at least two weeks of depressed mood orloss of pleasure, in addition to other symptoms. Thus, the skilledartisan will recognize that the present invention is useful for thetreatment of either a single episode or recurrent episodes of majordepressive disorder.

The skilled artisan will appreciate that other depressive disorders mayalso be treated by administering an effective amount of a compound ofFormula (I). Such other depressive disorders include dysthymic disorder,and depressive disorders not otherwise specified (for example,premenstrual dysphoric disorder, minor depressive disorder, recurrentbrief depressive disorder, or postpsychotic depressive disorder ofschizophrenia). In addition, the treatment of depression by thecompounds of Formula (I) may also include the treatment of mooddisorders due to a general medical condition and substance-induced mooddisorders.

The DSM-IV™ also provides a diagnostic tool for anxiety and relateddisorders. These disorders include: panic disorder with or withoutagoraphobia, agoraphobia without history of panic disorder, specificphobia, social phobia or social anxiety disorder, obsessive-compulsivedisorder, post-traumatic stress disorder, acute stress disorder,generalized anxiety disorder, anxiety disorder due to a general medicalcondition, substance-induced anxiety disorder and anxiety disorder nototherwise specified. As used herein, the term “anxiety” includestreatment of those anxiety disorders and related disorders described inthe DSM-IV.

1. A compound of Formula I:

wherein: D¹ is a C₁–C₃ alkane-diyl; D² is CH or nitrogen; D⁴ is oxygenor sulffir; R¹ is phenyl, which is optionally substituted with one tothree substitutents independently selected from the group consisting ofhalo, C₁–C₄ alkyl, C₁–C₄ alkoxy, cyano, difluoromethyl, trifluoromethyl,and trifluoromethoxy; R⁴ is a radical selected from the group consistingof:

wherein A¹, A², A³, and A⁴, together with the atoms to which they areattached, form an unsaturated heterocyclic ring in which each of A¹, A²,and A³ is independently CR⁷, nitrogen, which nitrogen is optionallysubstituted with R⁸, oxygen, or sulfur, and A⁴ is carbon or nitrogen,wherein only one of A¹, A², and A³ can be oxygen or sulfur; A⁵, A⁶, A⁷,and A⁸, together with the atoms to which they are attached, form anunsaturated carbocyclic or heterocyclic ring in which each of A⁵, A⁶,A⁷, and A⁸ is independently CR⁷ or nitrogen, wherein at least one of A⁵,A⁶, A⁷, and A⁸ must be CR⁷; each R⁷ is independently selected from thegroup consisting of hydrogen, halo, C₁–C⁴ alkyl, substituted C₁–C₄alkyl, C₃–C₆ cycloalkyl, C₁–C₄ alkoxycarbonyl, trifluoromethyl,trifluoromethoxy, and —NR⁹R¹⁰; R⁹ and R¹⁰ are each independentlyhydrogen, C₁–C₄ alkyl, or —C(O)—CH₃, or R⁹ and R¹⁰, together with thenitrogen to which they are attached, form a 4–7 membered saturatedheterocyclic ring; each R⁸ is independently selected from the groupconsisting of hydrogen, C₁–C₄ alkyl, substituted C₁–C₄ alkyl, and C₁–C₃cycloalkyl; R⁶ is C₁–C₄ alkyl, C₃–C₆ cycloalkyl, phenyl, or pyridyl,which phenyl or pyridyl is optionally substituted with one to threesubstituents independently selected from the group consisting of halo,cyano, C₁–C₄ alkyl, C₁–C₄ alkoxy, trifluoromethyl, trifluoromethoxy, and—NR¹¹R¹²; R¹¹ and R¹² are each independently hydrogen or C₁–C₄ alkyl, orR¹¹ and R¹², together with the nitrogen to which they are attached, forma 4–7 membered saturated heterocyclic ring; R⁵ is hydrogen, halo,trifluoromethyl, C₁–C₄ alkyl, C₃–C₆ cycloalkyl, furyl, thienyl,pyrrolyl, imidazolyl, —NR¹³R¹⁴, pyridyloxy, phenyl, phenoxy, phenylthio,anilino, which phenyl, phenoxy, phenylthio, or anilino group may beoptionally substituted on the phenyl ring with one or two substituentsindependently selected from the group consisting of halo, C₁–C₄ alkyl,C₁–C₄ alkoxy, and —S(O)_(q)(C₁–C₄ alkyl), or a radical selected from thegroup consisting of:

wherein W is a bond, CHR¹⁵, O, NR¹⁵, or S(O)_(q); q is 0, 1, or 2; R¹⁵is selected from the group consisting of hydrogen, C₁–C₄ alkyl, acetyl,carbamoyl, phenyl, benzyl, and —S(O)₂CH₃; Z¹, Z², and Z³ are eachindependently CH or nitrogen; R¹³ and R¹⁴ are each independentlyhydrogen or C₁–C₄ alkyl; or a pharmaceutically acceptable salt thereof.2. The compound of claim 1 wherein D¹ is methylene or ethane-1,1-diyl;D² is CH or nitrogen; D⁴ is oxygen; R¹ is phenyl, which is optionallysubstituted with one or two substituents independently selected from thegroup consisting of halo, C₁–C₄ alkyl, C₁–C₄ alkyoxy, trifluoromethyl,and trifluoromethoxy; R⁴ is a radical selected from the group consistingof:

wherein A¹ is CR⁷, A² is nitrogen, A³ is oxygen, and A⁴ is carbon; A¹ isCR⁷, A² is oxygen, A³ is nitrogen, and A⁴ is carbon; A¹ is oxygen, A² isnitrogen, A³ is CR⁷, and A⁴ is carbon; A¹ is oxygen, A² is CR⁷, A³ isnitrogen, and A⁴ is carbon; A¹ is nitrogen, A² is nitrogen, A³ is NR⁸,and A⁴ is carbon; A¹ is NR⁸, A² is nitrogen, A³ is nitrogen, and A⁴ iscarbon; A¹ is CR⁷, A² is nitrogen, A³ is nitrogen, and A⁴ is nitrogen;A¹ is nitrogen, A² is CR⁷, A³ is CR⁷, and A⁴is nitrogen; A¹ is NR⁸, A²is nitrogen, A³ is CR⁷, and A⁴ is carbon; A¹ is nitrogen, A² is NR⁸, A³is CR⁷, and A⁴ is carbon; A¹ is CR⁷, A² is NR⁸, A³ is nitrogen, and A⁴is carbon; A¹ is CR⁷, A² is nitrogen, A³ is NR⁸, and A⁴ is carbon; A⁵ isCR⁷, A⁶ is CR⁷, A⁷ is nitrogen, and A⁸ is nitrogen; A⁵ is CR⁷, A⁶ isCR⁷, A⁷ is CR⁷, and A⁸ is nitrogen; or A⁵ is CR⁷, A⁶ is CR⁷, A⁷ is CR⁷,and A⁸ is CR⁷; each R⁷ is independently selected from the groupconsisting of hydrogen, C₁–C₄ alkyl, substituted C₁–C₄ alkyl, C₃–C₆cycloalkyl, C₁–C₄ alkoxycarbonyl, and —NR⁹R¹⁰; R⁹ and R¹⁰ are eachindependently hydrogen, or C₁–C₄ alkyl, or R⁹ and R¹⁰, together with thenitrogen to which they are attached, form a 4–7 membered saturatedheterocyclic ring; each R⁸ is independently selected from the groupconsisting of hydrogen, C₁–C₄ alkyl, and substituted C₁–C₄ alkyl; R⁶ isphenyl or pyridyl, which phenyl or pyridyl is optionally substitutedwith one to two substituents independently selected from the groupconsisting of halo, and trifluoromethyl; R⁵ is hydrogen, halo, C₁–C₄alkyl, imidazolyl, —NR¹³R¹⁴, phenyl, or a radical selected from thegroup consisting of:

wherein W is —CHR¹⁵—, —O—, —NR¹⁵—, or S(O)_(q)—; q is 0, 1, or 2; R¹⁵ isselected from the group consisting of C₁–C₄ alkyl, and carbamoyl; Z¹,Z², and Z³ are each independently CH or nitrogen; R¹³ and R¹⁴ are eachindependently C₁–C₄ alkyl; or a pharmaceutically acceptable saltthereof.
 3. The compound of claim 1 wherein D¹ is methylene orethane-1,1-diyl; D^(2 is CH or nitrogen;) D⁴ is oxygen; R¹ is phenyl,which is optionally substituted with one or two substituentsindependently selected from the group consisting of halo, C₁–C₄ alkyl,C₁–C₄ alkyoxy, trifluoromethyl, and trifluoromethoxy; R⁴ is a radicalselected from the group consisting of:

each R⁷ is independently selected from the group consisting of hydrogen,C₁–C₄ alkyl, substituted C₁–C₄ alkyl, C₃–C₆ cycloalkyl, C₁–C₄alkoxycarbonyl, and —NR⁹R¹⁰; R⁹ and R¹⁰ are each independently hydrogen,or C₁–C₄ alkyl, or R⁹ and R¹⁰, together with the nitrogen to which theyare attached, form a 4–7 membered saturated heterocyclic ring; each R⁸is independently selected from the group consisting of hydrogen, C₁–C₄alkyl, and substituted C₁–C₄ alkyl; R⁶ is phenyl or pyridyl, whichphenyl or pyridyl is optionally substituted with one to two substituentsindependently selected from the group consisting of halo, andtrifluoromethyl; R⁵ is hydrogen, halo, C₁–C₄ alkyl, imidazolyl,—NR¹³R¹⁴, phenyl, or a radical selected from the group consisting of:

wherein W is —CHR¹⁵—, —O—, —NR¹⁵—, or —S(O)_(q)—; q is 0, 1, or 2; R¹⁵is selected from the group consisting of C₁–C₄ alkyl, and carbamoyl; Z¹,Z², and Z³ are each independently CH or nitrogen; R¹³ and R¹⁴ are eachindependently C₁–C₄ alkyl; or a pharmaceutically acceptable saltthereof.
 4. The compound of claim 1 wherein D² is nitrogen.
 5. Thecompound of claim 1 wherein D¹ is methylene.
 6. The compound of claim 1wherein R¹ is 3,5-bis-trifluoromethyl-phenyl.
 7. The compound of claim 1wherein R⁶ is phenyl, which is substituted with one halo ortrifluoromethyl.
 8. The compound of claim 7 wherein R⁶ is2-chloro-phenyl.
 9. The compound of claim 1 wherein R⁵ is imidazolyl ora radical of Formula (ID).
 10. The compound of claim 9 wherein R⁵ isimidazolyl.
 11. The compound of claim 9 wherein R⁵ is a radical ofFormula (ID) in which Z² is nitrogen.
 12. The compound of claim 1wherein R⁴ is a radical of Formula (IA).
 13. The compound of claim 12wherein R⁴ is a radical selected from the group consisting of:


14. The compound of claim 1 wherein the compound is selected from thegroup consisting of:[1-(3,5-bis-trifluoromethylbenzyl)-5-imidazol-1-yl-1H-[1,2,3]triazol-4-yl]-[5-(2-chlorophenyl)-3-hydroxymethyl-isoxazol-4-yl]-methanone,[1-(3,5-bis-trifluoromethyl-benzyl)-5-imidazol-1-yl-1H-[1,2,3]triazol-4-yl]-[4-(2-chloro-phenyl)-2-cyclopropyl-oxazol-5-yl]-methanone,[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-3-(1-hydroxy-1-methyl-ethyl)-isoxazol-4-yl]-methanone,[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyrimidin-5-yl-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-3-(1-hydroxy-1-methyl-ethyl)-isoxazol-4-yl]-methanone,[1-(3,5-bis-trifluoromethyl-benzyl)-5-imidazol-1-yl-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-3-methyl-isoxazol-4-yl]-methanone,[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-[4-(2-chloro-phenyl)-2-cyclopropyl-oxazol-5-yl]-methanone,[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-[4-(2-chloro-phenyl)-2-cyclopropyl-oxazol-5-yl]-methanone,[1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazol-4-yl]-[4-(2-chloro-phenyl)-1-methyl-1H-pyrazol-5-yl]-methanone,and[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-[3-(2-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-yl]-methanone,or a pharmaceutically acceptable salt thereof.
 15. A compound selectedfrom the group consisting of:{1-(3,5-Bis-trifluoromethyl-benzyl)-5-[(2-dimethylamino-ethyl)-methyl-amino]-1H-[1,2,3]triazol-4-yl}-[3-(2-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-yl]-methanone,[1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-{3-(2-chloro-phenyl)-5-[(2-morpholin-4-yl-ethylamino)-methyl]-isoxazol-4-yl}-methanone,1-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-3-(2-chloro-phenyl)-propenone,1-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-3-(2-fluoro-phenyl)-propenone,1-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-3-(2-chlorophenyl)-propan-1-one,and3-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-imidazol-1-yl-1H-[1,2,3]triazol-4-yl]-2-(2-chloro-benzoyl)-3-oxo-propionitrile,or a pharmaceutically acceptable salt thereof.
 16. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, in combination with a pharmaceuticallyacceptable carrier, excipient, or diluent.
 17. A method of treating acondition associated with an excess of tachykinins, wherein thecondition associated with an excess of tachykinins is selected from thegroup consisting of depression, anxiety, irritable bowel syndrome, andemesis comprising administering to a patient in need thereof aneffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof.
 18. The compound of claim 14 wherein thecompound is[1-(3,5-bis-trifluoromethylbenzyl)-5-imidazol-1-yl-1H-[1,2,3]triazol-4-yl]-[5-(2-chlorophenyl)-3-hydroxymethyl-isoxazol-4-yl]-methanone,or a pharmaceutically acceptable salt thereof.